TY  - THES
AU  - Mićanović, Dragica
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5458
AB  - Aronija (lat. Aronia melanocarpa), voće karakteristično po tamnim bobicama oporog ukusa, sadrži mnoštvo fenolnih jedinjenja zaslužnih za njena biološka svojstva. Vodeni ekstrakt ploda aronije (VEPA) pokazao je proinflamacijsko dejstvo. In vitro primena povećala je fagoctinu sposobnost makrofaga i stimulisala produkciju azot-monoksida iz dendritskih ćelija, kao i diferencijaciju proinflamacijskih CD4+ T limfocita. In vivo, oralni tretman zdravih miševa doveo je do promene distribucije ćelija imunskog sistema u crevu i povećane produkcije IFN-γ u slezini. Efekat VEPA na imunski sistem ispitan je u mišjim modelima infekcije unutarćelijskom bakterijom Listeria monocytogenes i melanoma, indukovanog subkutanim injeciranjem B16 ćelija. Pretretman VEPA ublažava kliničku sliku i doprinosi eliminaciji infekcije tako što na mestu inicijacije infekcije – u Pejerovim pločama i u ciljnom tkivu – slezini, povećava zastupljenost CD8+ T limfocita i makrofaga, pri čemu su efektorska svojstva makrofaga naročito stimulisana. U modelu melanoma pretretman VEPA smanjio je incidencu bolesti i zapreminu tumora, istovremeno povećavajući infiltraciju ćelija imunskog sistema u tumor. Zastupljenost NK ćelija, CD4+ i CD8+ T limfocita unutar tumora povećana je usled pretretmana VEPA, kao i ekspresija IFN-γ u ovim ćelijama, dok je zastupljenost supresivnih ćelija smanjena. Produkcija IFN-γ povećana je i u mezenteričnim limfnim čvorovima, slezini i serumu pretretiranih životinja. Splenociti ove grupe životinja pokazali su veću citotoksičnost prema ćelijama melanoma, zavisnu od IFN-γ. Izostanak direktnog uticaja na B16 ćelije dodatno ukazuje na imunomodulacijska svojstva VEPA. Ovi rezultati ukazuju na potencijal primene aronije u prevenciji stanja i bolesti u kojima je neophodna stimulacija proinflamacijskog imunskog odgovora.
AB  - Chokeberry (Aronia melanocarpa), fruit with black berries that leave an astringent mouthfeel after consumption, is rich in polyphenols responsible for its bioactive properties. Chokeberry extract (VEPA) showed profound in vitro and in vivo pro-inflammatory effects. When applied in vitro, VEPA stimulated phagocytic ability of macrophages and NO production from dendritic cells, as well as differentiation of pro-inflammatory CD4+ T cells. In vivo oral treatment of healthy mice changed the distribution of immune cells within the gut and increased production of IFN-γ in the spleen. In the mouse model of infection with intracellular bacteria Listeria monocytogenes VEPA accelerated eradication of infection and improved their general appearance. Also, VEPA pretreatment increased proportions of macrophages and CD8+ T cells both in the gut and the spleen of infected mice and mainly affected effector functions of macrophages. In the mouse model of melanoma, induced by subcutaneous injection of B16 cells, VEPA delayed melanoma appearance, decreased tumor volume and increased infiltration of immune cells in the tumor. Proportion of NK cells, CD4+ and CD8+ T cells within the tumor was increased, as well as the expression of IFN-γ within these cells, with downregulated frequency of cells that suppress the immune cells. Additionally, the production of IFN-γ was enhanced in the mesenteric lymph nodes, spleen and the serum of pretreated animals. Splenocytes from these animals showed enhanced cytotoxicity towards melanoma cells, dependent on IFN-γ. These results point to the applicative potential of VEPA in the prevention of different states and diseases where an enhanced pro-inflammatory response is needed.
PB  - Belgrade: Faculty of Biology, University of Belgrade
T2  - Faculty of Biology, University of Belgrade
T1  - Uticaj vodenog ekstrakta ploda aronije na imunski sistem u mišjim modelima infekcije i melanoma
T1  - Effects of chokeberry fruit water extract on the immune system in mouse models of infection and melanoma
EP  - 110
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5458
ER  - 

@phdthesis{
author = "Mićanović, Dragica",
year = "2023",
abstract = "Aronija (lat. Aronia melanocarpa), voće karakteristično po tamnim bobicama oporog ukusa, sadrži mnoštvo fenolnih jedinjenja zaslužnih za njena biološka svojstva. Vodeni ekstrakt ploda aronije (VEPA) pokazao je proinflamacijsko dejstvo. In vitro primena povećala je fagoctinu sposobnost makrofaga i stimulisala produkciju azot-monoksida iz dendritskih ćelija, kao i diferencijaciju proinflamacijskih CD4+ T limfocita. In vivo, oralni tretman zdravih miševa doveo je do promene distribucije ćelija imunskog sistema u crevu i povećane produkcije IFN-γ u slezini. Efekat VEPA na imunski sistem ispitan je u mišjim modelima infekcije unutarćelijskom bakterijom Listeria monocytogenes i melanoma, indukovanog subkutanim injeciranjem B16 ćelija. Pretretman VEPA ublažava kliničku sliku i doprinosi eliminaciji infekcije tako što na mestu inicijacije infekcije – u Pejerovim pločama i u ciljnom tkivu – slezini, povećava zastupljenost CD8+ T limfocita i makrofaga, pri čemu su efektorska svojstva makrofaga naročito stimulisana. U modelu melanoma pretretman VEPA smanjio je incidencu bolesti i zapreminu tumora, istovremeno povećavajući infiltraciju ćelija imunskog sistema u tumor. Zastupljenost NK ćelija, CD4+ i CD8+ T limfocita unutar tumora povećana je usled pretretmana VEPA, kao i ekspresija IFN-γ u ovim ćelijama, dok je zastupljenost supresivnih ćelija smanjena. Produkcija IFN-γ povećana je i u mezenteričnim limfnim čvorovima, slezini i serumu pretretiranih životinja. Splenociti ove grupe životinja pokazali su veću citotoksičnost prema ćelijama melanoma, zavisnu od IFN-γ. Izostanak direktnog uticaja na B16 ćelije dodatno ukazuje na imunomodulacijska svojstva VEPA. Ovi rezultati ukazuju na potencijal primene aronije u prevenciji stanja i bolesti u kojima je neophodna stimulacija proinflamacijskog imunskog odgovora., Chokeberry (Aronia melanocarpa), fruit with black berries that leave an astringent mouthfeel after consumption, is rich in polyphenols responsible for its bioactive properties. Chokeberry extract (VEPA) showed profound in vitro and in vivo pro-inflammatory effects. When applied in vitro, VEPA stimulated phagocytic ability of macrophages and NO production from dendritic cells, as well as differentiation of pro-inflammatory CD4+ T cells. In vivo oral treatment of healthy mice changed the distribution of immune cells within the gut and increased production of IFN-γ in the spleen. In the mouse model of infection with intracellular bacteria Listeria monocytogenes VEPA accelerated eradication of infection and improved their general appearance. Also, VEPA pretreatment increased proportions of macrophages and CD8+ T cells both in the gut and the spleen of infected mice and mainly affected effector functions of macrophages. In the mouse model of melanoma, induced by subcutaneous injection of B16 cells, VEPA delayed melanoma appearance, decreased tumor volume and increased infiltration of immune cells in the tumor. Proportion of NK cells, CD4+ and CD8+ T cells within the tumor was increased, as well as the expression of IFN-γ within these cells, with downregulated frequency of cells that suppress the immune cells. Additionally, the production of IFN-γ was enhanced in the mesenteric lymph nodes, spleen and the serum of pretreated animals. Splenocytes from these animals showed enhanced cytotoxicity towards melanoma cells, dependent on IFN-γ. These results point to the applicative potential of VEPA in the prevention of different states and diseases where an enhanced pro-inflammatory response is needed.",
publisher = "Belgrade: Faculty of Biology, University of Belgrade",
journal = "Faculty of Biology, University of Belgrade",
title = "Uticaj vodenog ekstrakta ploda aronije na imunski sistem u mišjim modelima infekcije i melanoma, Effects of chokeberry fruit water extract on the immune system in mouse models of infection and melanoma",
pages = "110",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5458"
}

Mićanović, D.. (2023). Uticaj vodenog ekstrakta ploda aronije na imunski sistem u mišjim modelima infekcije i melanoma. in Faculty of Biology, University of Belgrade
Belgrade: Faculty of Biology, University of Belgrade..
https://hdl.handle.net/21.15107/rcub_ibiss_5458

Mićanović D. Uticaj vodenog ekstrakta ploda aronije na imunski sistem u mišjim modelima infekcije i melanoma. in Faculty of Biology, University of Belgrade. 2023;:null-110.
https://hdl.handle.net/21.15107/rcub_ibiss_5458 .

Mićanović, Dragica, "Uticaj vodenog ekstrakta ploda aronije na imunski sistem u mišjim modelima infekcije i melanoma" in Faculty of Biology, University of Belgrade (2023),
https://hdl.handle.net/21.15107/rcub_ibiss_5458 .

TY  - CONF
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
PY  - 2022
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5294
AB  - The impact of the technology is a hallmark of a new era in molecular medicine, but,
paradoxically, it has not resulted in improved understanding of numerous degenerative/
proliferative diseases. Built on such a platform, highly specific oncotherapy aimed at the
malignant phenotype, or constituents of the tumor microenvironment from stromal to
endothelial and immune-infiltrating cells, was supposed to bring a revolutionary turn in
treatment. Instead, inadequate achievements and unclear correlations between individual
response to treatment and expression of relevant molecules in tumor tissue remind
us that, despite all biotechnological advances, understanding of disease pathology is still
very limited, while breaking down biological systems into molecular dimensions has
obscured meaning and functionality of the whole. This primarily refers to high-grade
tumors characterized by a fraction of low-differentiated cells, significant heterogeneity
of cell phenotypes and aggressive characteristics of the tumor microenvironment. As
the criterion of low general toxicity, which essentially represented the most important
advantage of molecular therapies and the main motive in their creation, is not satisfied,
the treatment often ends with the choice of non-selective chemotherapy or radiotherapy.
The limited success of aggressive treatments in advanced malignancies is closely
related to tumor repopulation in response to such treatments. This effect brought to
the surface a sophisticated communication network within the tumor tissue, revealing
intense contacts between vital and dying cells, which are profiled as the most important
stimulus in maintaining the continuity of life of the tumor mass. The possibilities of
getting out of this loop and leaving the vicious circle of death and division in the tumor,
as well as the potential of plants to stimulate the process of establishing new biological
balance and improve the effects of current therapy, will be discussed in this study.
AB  - Снажан утицај технологије обележје је нове ере у медицини, али, наизглед па-
радоксално, није резултирао суштинским искораком у разумевању и лечењу низа
болести дегенеративног или пролиферативног карактера. Изграђена на оваквој
платформи, високоспецифична онкотерапија усмерена на малигни фенотип или
конституенте туморског микроокружења од стромалних до ендотелних и иму-
но-инфилтрирајућих ћелија, требало је да донесе револуционарни заокрет у ле-
чењу. Уместо тога, неадекватна достигнућа и нејасна корелација између инди-
видуалног одговора на примењени третман и експресије релевантних молекула
у туморском ткиву подсећају нас да је, и поред свих биотехнолошких искорака,
разумевање патологије болести и даље веома ограничено, док је рашчлањивање
биолошких система на молекуларне димензије замаглило сагледавање смисла и
функционалности целине. Ово се пре свега односи на туморе високог градуса
које карактерише фракција нискодиферентованих ћелија, значајна хетерогеност
ћелијских фенотипова, агресивне карактеристике туморског микроокружења и
висок метастатски потенцијал. Како ни критеријум ниске опште токсичности
који је суштински представљао и најважнију предност молекуларних терапија и
главни мотив у њиховом креирању није задовољен, лечење се, не ретко, завршава
избором неселективне хемо- или радио- терапије. Ограничени успех аресивних
видова лечења код узнапредовалих малигнитета уско је повезан са репопулаци-
јом тумора у одговору на овакве третмане. Поменути ефекат је извукао на повр-
шину софистицирану комуникациону мрежу унутар ткива тумора, откривајући
интензивне контакте између виталних и умирућих ћелија, који се профилишу
као најнажнији стимулус у одржавању континуитета живота туморске масе. О
могућностима изласка из ове петље и напуштања зачараног круга смрти и деобе
у тумору, као и потенцијалу биљака да подстакну процес успостављања нове био-
лошке равнотеже и унапреде ефекте актуелне терапије, биће дискутовано у овој
студији.
PB  - Serbian Society for Immunology, Molecular Oncology and Regenerative Medicine
C3  - Abstract Book: First Serbian molecular medicine congress; 2022 Jun 16-18; Foča, Bosnia and Herzegovina
T1  - Altruistic behavior of the cells – the seed of tumor progression and new terapeutic platform
SP  - 132
EP  - 133
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5294
ER  - 

@conference{
author = "Mijatović, Sanja and Maksimović-Ivanić, Danijela",
year = "2022",
abstract = "The impact of the technology is a hallmark of a new era in molecular medicine, but,
paradoxically, it has not resulted in improved understanding of numerous degenerative/
proliferative diseases. Built on such a platform, highly specific oncotherapy aimed at the
malignant phenotype, or constituents of the tumor microenvironment from stromal to
endothelial and immune-infiltrating cells, was supposed to bring a revolutionary turn in
treatment. Instead, inadequate achievements and unclear correlations between individual
response to treatment and expression of relevant molecules in tumor tissue remind
us that, despite all biotechnological advances, understanding of disease pathology is still
very limited, while breaking down biological systems into molecular dimensions has
obscured meaning and functionality of the whole. This primarily refers to high-grade
tumors characterized by a fraction of low-differentiated cells, significant heterogeneity
of cell phenotypes and aggressive characteristics of the tumor microenvironment. As
the criterion of low general toxicity, which essentially represented the most important
advantage of molecular therapies and the main motive in their creation, is not satisfied,
the treatment often ends with the choice of non-selective chemotherapy or radiotherapy.
The limited success of aggressive treatments in advanced malignancies is closely
related to tumor repopulation in response to such treatments. This effect brought to
the surface a sophisticated communication network within the tumor tissue, revealing
intense contacts between vital and dying cells, which are profiled as the most important
stimulus in maintaining the continuity of life of the tumor mass. The possibilities of
getting out of this loop and leaving the vicious circle of death and division in the tumor,
as well as the potential of plants to stimulate the process of establishing new biological
balance and improve the effects of current therapy, will be discussed in this study., Снажан утицај технологије обележје је нове ере у медицини, али, наизглед па-
радоксално, није резултирао суштинским искораком у разумевању и лечењу низа
болести дегенеративног или пролиферативног карактера. Изграђена на оваквој
платформи, високоспецифична онкотерапија усмерена на малигни фенотип или
конституенте туморског микроокружења од стромалних до ендотелних и иму-
но-инфилтрирајућих ћелија, требало је да донесе револуционарни заокрет у ле-
чењу. Уместо тога, неадекватна достигнућа и нејасна корелација између инди-
видуалног одговора на примењени третман и експресије релевантних молекула
у туморском ткиву подсећају нас да је, и поред свих биотехнолошких искорака,
разумевање патологије болести и даље веома ограничено, док је рашчлањивање
биолошких система на молекуларне димензије замаглило сагледавање смисла и
функционалности целине. Ово се пре свега односи на туморе високог градуса
које карактерише фракција нискодиферентованих ћелија, значајна хетерогеност
ћелијских фенотипова, агресивне карактеристике туморског микроокружења и
висок метастатски потенцијал. Како ни критеријум ниске опште токсичности
који је суштински представљао и најважнију предност молекуларних терапија и
главни мотив у њиховом креирању није задовољен, лечење се, не ретко, завршава
избором неселективне хемо- или радио- терапије. Ограничени успех аресивних
видова лечења код узнапредовалих малигнитета уско је повезан са репопулаци-
јом тумора у одговору на овакве третмане. Поменути ефекат је извукао на повр-
шину софистицирану комуникациону мрежу унутар ткива тумора, откривајући
интензивне контакте између виталних и умирућих ћелија, који се профилишу
као најнажнији стимулус у одржавању континуитета живота туморске масе. О
могућностима изласка из ове петље и напуштања зачараног круга смрти и деобе
у тумору, као и потенцијалу биљака да подстакну процес успостављања нове био-
лошке равнотеже и унапреде ефекте актуелне терапије, биће дискутовано у овој
студији.",
publisher = "Serbian Society for Immunology, Molecular Oncology and Regenerative Medicine",
journal = "Abstract Book: First Serbian molecular medicine congress; 2022 Jun 16-18; Foča, Bosnia and Herzegovina",
title = "Altruistic behavior of the cells – the seed of tumor progression and new terapeutic platform",
pages = "132-133",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5294"
}

Mijatović, S.,& Maksimović-Ivanić, D.. (2022). Altruistic behavior of the cells – the seed of tumor progression and new terapeutic platform. in Abstract Book: First Serbian molecular medicine congress; 2022 Jun 16-18; Foča, Bosnia and Herzegovina
Serbian Society for Immunology, Molecular Oncology and Regenerative Medicine., 132-133.
https://hdl.handle.net/21.15107/rcub_ibiss_5294

Mijatović S, Maksimović-Ivanić D. Altruistic behavior of the cells – the seed of tumor progression and new terapeutic platform. in Abstract Book: First Serbian molecular medicine congress; 2022 Jun 16-18; Foča, Bosnia and Herzegovina. 2022;:132-133.
https://hdl.handle.net/21.15107/rcub_ibiss_5294 .

Mijatović, Sanja, Maksimović-Ivanić, Danijela, "Altruistic behavior of the cells – the seed of tumor progression and new terapeutic platform" in Abstract Book: First Serbian molecular medicine congress; 2022 Jun 16-18; Foča, Bosnia and Herzegovina (2022):132-133,
https://hdl.handle.net/21.15107/rcub_ibiss_5294 .

TY  - THES
AU  - Krajnović, Tamara
PY  - 2021
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4670
AB  - Izoksantohumol (IXN), prenilflavonoid iz hmelja, poseduje spektar bioloških aktivnosti značajnih za tretman brojnih patoloških stanja. U ovoj studiji ispitivan je njegov uticaj na modelima solidnog i metastatskog melanoma in vitro i in vivo, u kontekstu samostalnog delovanja na ćelije melanoma različite agresivnosti i interakcije sa hemioterapijom. Pokazano je da su efekti IXN bili postojani na svim ćelijskim linijama melanoma ‒ od nisko invazivne forme B16 poreklom iz miša, preko visoko invazivne linije humanog porekla A-375, do metastatskog klona B16-F10. Pored inhibicije proliferacije uočene na svim linijama, tretman IXN doveo je do diferencijacije i gubitka pluripotentnih svojstava B16 i A-375 ćelija, uz prisustvo apoptoze i značajne promene u signalnim putevima relevantnim za ove procese. Sa druge strane, IXN je uz indukciju programirane ćelijske smrti tipa I i II na klonu B16-F10, smanjio klonogeni potencijal populacije preživelih ćelija i, narušavajući integrinsku signalizaciju, redukovao adhezivnost, migratornost i invazivnost. Pored jasnog trenda u supresiji solidnog, a posebno metastatskog melanoma, IXN je potencirao delovanje paklitaksela (PCT) in vitro i in vivo. Za razliku od paralelnog tretmana, aplikovanje IXN 7 sukcesivnih dana pre početka hemioterapije učinilo je efikasnom subterapeutsku dozu PCT u modelu singenog metastatskog melanoma. Ovaj podatak je, uz histopatološku potvrdu promene fenotipa ćelija u metastazama, podvukao važnost indukcije diferencijacije u kasnijem učinku hemioterapije. Opisani rezultati predstavljaju prvi dokaz antitumorske aktivnosti IXN in vivo, kao i značajan doprinos novom konceptu diferencijacione terapije u lečenju solidnih i metastatskih maligniteta.
AB  - Isoxanthohumol (IXN), a prenylflavonoid from hops, owns a spectrum of biological activities important for the therapy of numerous pathological conditions. In this study, its influence on solid and metastatic melanoma models in vitro and in vivo was investigated, in the context of independent action on melanoma cells of different aggressiveness and interaction with chemotherapy. The effects of IXN were consistent in all cell lines ‒ from the low-invasive mouse-derived B16 form and highly invasive line of human origin A-375 to metastatic clone B16-F10. In addition to proliferation inhibition observed in all cell lines, IXN treatment led to differentiation and loss of pluripotent properties of B16 and A-375 cells, with the presence of apoptosis and significant changes in signaling pathways relevant to these processes. On the other hand, along with induction of apoptosis and autophagy in B16-F10 clones, IXN decreased the clonogenic potential in the population of surviving cells and, by disrupting integrin signaling, reduced adhesion, migration and, invasiveness. Aside from a clear trend in the suppression of solid and metastatic melanoma, IXN potentiated the action of paclitaxel (PCT) in vitro and in vivo. Unlike concomitant treatment, the 7-days application of IXN before the start of chemotherapy made the subtherapeutic dose of PCT effective in the metastatic melanoma model. This data, along with histopathological confirmation of changes in cells’ phenotype in metastases, underlined the importance of induction of differentiation for chemotherapy outcome. The described results represent the first proof of IXN antitumor activity in vivo, as well as a significant contribution to a new concept of differentiation therapy in the treatment of solid and metastatic malignancies.
PB  - Belgrade: Faculty of Biology, University of Belgrade
T2  - Faculty of Biology, University of Belgrade
T1  - Efekti izoksantohumola na tretman solidnog i metastatskog melanoma: direktan uticaj i interakcija sa hemioterapijom
T1  - Effects of isoxanthohumol on the treatment of solid and metastatic melanoma: direct impact and interaction with chemotherapy
SP  - 1
EP  - 112
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_4670
ER  - 

@phdthesis{
author = "Krajnović, Tamara",
year = "2021",
abstract = "Izoksantohumol (IXN), prenilflavonoid iz hmelja, poseduje spektar bioloških aktivnosti značajnih za tretman brojnih patoloških stanja. U ovoj studiji ispitivan je njegov uticaj na modelima solidnog i metastatskog melanoma in vitro i in vivo, u kontekstu samostalnog delovanja na ćelije melanoma različite agresivnosti i interakcije sa hemioterapijom. Pokazano je da su efekti IXN bili postojani na svim ćelijskim linijama melanoma ‒ od nisko invazivne forme B16 poreklom iz miša, preko visoko invazivne linije humanog porekla A-375, do metastatskog klona B16-F10. Pored inhibicije proliferacije uočene na svim linijama, tretman IXN doveo je do diferencijacije i gubitka pluripotentnih svojstava B16 i A-375 ćelija, uz prisustvo apoptoze i značajne promene u signalnim putevima relevantnim za ove procese. Sa druge strane, IXN je uz indukciju programirane ćelijske smrti tipa I i II na klonu B16-F10, smanjio klonogeni potencijal populacije preživelih ćelija i, narušavajući integrinsku signalizaciju, redukovao adhezivnost, migratornost i invazivnost. Pored jasnog trenda u supresiji solidnog, a posebno metastatskog melanoma, IXN je potencirao delovanje paklitaksela (PCT) in vitro i in vivo. Za razliku od paralelnog tretmana, aplikovanje IXN 7 sukcesivnih dana pre početka hemioterapije učinilo je efikasnom subterapeutsku dozu PCT u modelu singenog metastatskog melanoma. Ovaj podatak je, uz histopatološku potvrdu promene fenotipa ćelija u metastazama, podvukao važnost indukcije diferencijacije u kasnijem učinku hemioterapije. Opisani rezultati predstavljaju prvi dokaz antitumorske aktivnosti IXN in vivo, kao i značajan doprinos novom konceptu diferencijacione terapije u lečenju solidnih i metastatskih maligniteta., Isoxanthohumol (IXN), a prenylflavonoid from hops, owns a spectrum of biological activities important for the therapy of numerous pathological conditions. In this study, its influence on solid and metastatic melanoma models in vitro and in vivo was investigated, in the context of independent action on melanoma cells of different aggressiveness and interaction with chemotherapy. The effects of IXN were consistent in all cell lines ‒ from the low-invasive mouse-derived B16 form and highly invasive line of human origin A-375 to metastatic clone B16-F10. In addition to proliferation inhibition observed in all cell lines, IXN treatment led to differentiation and loss of pluripotent properties of B16 and A-375 cells, with the presence of apoptosis and significant changes in signaling pathways relevant to these processes. On the other hand, along with induction of apoptosis and autophagy in B16-F10 clones, IXN decreased the clonogenic potential in the population of surviving cells and, by disrupting integrin signaling, reduced adhesion, migration and, invasiveness. Aside from a clear trend in the suppression of solid and metastatic melanoma, IXN potentiated the action of paclitaxel (PCT) in vitro and in vivo. Unlike concomitant treatment, the 7-days application of IXN before the start of chemotherapy made the subtherapeutic dose of PCT effective in the metastatic melanoma model. This data, along with histopathological confirmation of changes in cells’ phenotype in metastases, underlined the importance of induction of differentiation for chemotherapy outcome. The described results represent the first proof of IXN antitumor activity in vivo, as well as a significant contribution to a new concept of differentiation therapy in the treatment of solid and metastatic malignancies.",
publisher = "Belgrade: Faculty of Biology, University of Belgrade",
journal = "Faculty of Biology, University of Belgrade",
title = "Efekti izoksantohumola na tretman solidnog i metastatskog melanoma: direktan uticaj i interakcija sa hemioterapijom, Effects of isoxanthohumol on the treatment of solid and metastatic melanoma: direct impact and interaction with chemotherapy",
pages = "1-112",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_4670"
}

Krajnović, T.. (2021). Efekti izoksantohumola na tretman solidnog i metastatskog melanoma: direktan uticaj i interakcija sa hemioterapijom. in Faculty of Biology, University of Belgrade
Belgrade: Faculty of Biology, University of Belgrade., 1-112.
https://hdl.handle.net/21.15107/rcub_ibiss_4670

Krajnović T. Efekti izoksantohumola na tretman solidnog i metastatskog melanoma: direktan uticaj i interakcija sa hemioterapijom. in Faculty of Biology, University of Belgrade. 2021;:1-112.
https://hdl.handle.net/21.15107/rcub_ibiss_4670 .

Krajnović, Tamara, "Efekti izoksantohumola na tretman solidnog i metastatskog melanoma: direktan uticaj i interakcija sa hemioterapijom" in Faculty of Biology, University of Belgrade (2021):1-112,
https://hdl.handle.net/21.15107/rcub_ibiss_4670 .

TY  - JOUR
AU  - Mićanović, Dragica
AU  - Saksida, Tamara
AU  - Koprivica, Ivan
AU  - Vujičić, Milica
AU  - Despotović, Sanja
AU  - Šavikin, Katarina
AU  - Janković, Teodora
AU  - Stojanović, Ivana D.
PY  - 2020
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3591
AB  - Chokeberry (Aronia melanocarpa) is known for its anti-oxidant, anti-inflammatory and anti-diabetic properties. Since the effects of chokeberry extract on the immune response have been only sporadically assessed, our aim was to investigate chokeberry fruit water extract on the immune response in vivo and in vitro. When administered orally to healthy mice, the extract exerted immunomodulatory effects in the gut evidenced by the altered proportion of macrophages, dendritic cells and T cells. Importantly, oral consumption of the chokeberry extract resulted in blood glucose level increase in C57BL/6 mice with chemically-induced diabetes. These in vivo results were corroborated by observed up-regulation of nitric oxide and interelukin-1β production in macrophages and dendritic cells, up-regulated phagocytic activity of macrophages, increased T and B lymphocytes proportions and differentiation of interferon-γ-producing T cells in vitro. The obtained results imply that our chokeberry extract stimulates pro-inflammatory properties in immune cells of innate and adaptive immunity.
PB  - Elsevier Ltd.
T2  - Journal of Functional Foods
T1  - Chokeberry (Aronia melanocarpa) fruit extract modulates immune response in vivo and in vitro
VL  - 66
DO  - 10.1016/j.jff.2020.103836
SP  - 103836
ER  - 

@article{
author = "Mićanović, Dragica and Saksida, Tamara and Koprivica, Ivan and Vujičić, Milica and Despotović, Sanja and Šavikin, Katarina and Janković, Teodora and Stojanović, Ivana D.",
year = "2020",
abstract = "Chokeberry (Aronia melanocarpa) is known for its anti-oxidant, anti-inflammatory and anti-diabetic properties. Since the effects of chokeberry extract on the immune response have been only sporadically assessed, our aim was to investigate chokeberry fruit water extract on the immune response in vivo and in vitro. When administered orally to healthy mice, the extract exerted immunomodulatory effects in the gut evidenced by the altered proportion of macrophages, dendritic cells and T cells. Importantly, oral consumption of the chokeberry extract resulted in blood glucose level increase in C57BL/6 mice with chemically-induced diabetes. These in vivo results were corroborated by observed up-regulation of nitric oxide and interelukin-1β production in macrophages and dendritic cells, up-regulated phagocytic activity of macrophages, increased T and B lymphocytes proportions and differentiation of interferon-γ-producing T cells in vitro. The obtained results imply that our chokeberry extract stimulates pro-inflammatory properties in immune cells of innate and adaptive immunity.",
publisher = "Elsevier Ltd.",
journal = "Journal of Functional Foods",
title = "Chokeberry (Aronia melanocarpa) fruit extract modulates immune response in vivo and in vitro",
volume = "66",
doi = "10.1016/j.jff.2020.103836",
pages = "103836"
}

Mićanović, D., Saksida, T., Koprivica, I., Vujičić, M., Despotović, S., Šavikin, K., Janković, T.,& Stojanović, I. D.. (2020). Chokeberry (Aronia melanocarpa) fruit extract modulates immune response in vivo and in vitro. in Journal of Functional Foods
Elsevier Ltd.., 66, 103836.
https://doi.org/10.1016/j.jff.2020.103836

Mićanović D, Saksida T, Koprivica I, Vujičić M, Despotović S, Šavikin K, Janković T, Stojanović ID. Chokeberry (Aronia melanocarpa) fruit extract modulates immune response in vivo and in vitro. in Journal of Functional Foods. 2020;66:103836.
doi:10.1016/j.jff.2020.103836 .

Mićanović, Dragica, Saksida, Tamara, Koprivica, Ivan, Vujičić, Milica, Despotović, Sanja, Šavikin, Katarina, Janković, Teodora, Stojanović, Ivana D., "Chokeberry (Aronia melanocarpa) fruit extract modulates immune response in vivo and in vitro" in Journal of Functional Foods, 66 (2020):103836,
https://doi.org/10.1016/j.jff.2020.103836 . .

TY  - CHAP
AU  - Vujičić, Milica
AU  - Despotović, Sanja
AU  - Saksida, Tamara
AU  - Stojanović, Ivana D.
AU  - Harris, James
AU  - Morand, Eric F.
PY  - 2020
UR  - http://link.springer.com/10.1007/978-1-4939-9936-1_17
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3535
AB  - Macrophage migration inhibitory factor (MIF) is a molecule with multiple functions: from enforcing the immune system to fight bacterial infection to the regulation of insulin activity. Also, MIF is expressed by enterocytes that line the intestinal border toward the lumen, and in M cells, where it regulates phagocytosis of antigens from the lumen of the gut and their transport to Peyer's patches. Since there were no data on the role of MIF in the maintenance of the intestinal barrier, we used MIF-deficient mice bred on C57BL/6 background as a model for the investigation of intestinal permeability. The obtained results indicate that the absence of MIF increases intestinal permeability. Here we describe two methods for measuring intestinal permeability in mice: detection of orally delivered FITC-dextran in the serum and transmission electron microscopy used for visualization and measurement of cell-to-cell connections width.
PB  - Humana, New York, NY
T2  - Macrophage Migration Inhibitory Factor
T1  - The Effect of Macrophage Migration Inhibitory Factor on Intestinal Permeability: FITC-Dextran Serum Measurement and Transmission Electron Microscopy.
DO  - 10.1007/978-1-4939-9936-1_17
SP  - 193
EP  - 201
ER  - 

@inbook{
author = "Vujičić, Milica and Despotović, Sanja and Saksida, Tamara and Stojanović, Ivana D. and Harris, James and Morand, Eric F.",
year = "2020",
abstract = "Macrophage migration inhibitory factor (MIF) is a molecule with multiple functions: from enforcing the immune system to fight bacterial infection to the regulation of insulin activity. Also, MIF is expressed by enterocytes that line the intestinal border toward the lumen, and in M cells, where it regulates phagocytosis of antigens from the lumen of the gut and their transport to Peyer's patches. Since there were no data on the role of MIF in the maintenance of the intestinal barrier, we used MIF-deficient mice bred on C57BL/6 background as a model for the investigation of intestinal permeability. The obtained results indicate that the absence of MIF increases intestinal permeability. Here we describe two methods for measuring intestinal permeability in mice: detection of orally delivered FITC-dextran in the serum and transmission electron microscopy used for visualization and measurement of cell-to-cell connections width.",
publisher = "Humana, New York, NY",
journal = "Macrophage Migration Inhibitory Factor",
booktitle = "The Effect of Macrophage Migration Inhibitory Factor on Intestinal Permeability: FITC-Dextran Serum Measurement and Transmission Electron Microscopy.",
doi = "10.1007/978-1-4939-9936-1_17",
pages = "193-201"
}

Vujičić, M., Despotović, S., Saksida, T., Stojanović, I. D., Harris, J.,& Morand, E. F.. (2020). The Effect of Macrophage Migration Inhibitory Factor on Intestinal Permeability: FITC-Dextran Serum Measurement and Transmission Electron Microscopy.. in Macrophage Migration Inhibitory Factor
Humana, New York, NY., 193-201.
https://doi.org/10.1007/978-1-4939-9936-1_17

Vujičić M, Despotović S, Saksida T, Stojanović ID, Harris J, Morand EF. The Effect of Macrophage Migration Inhibitory Factor on Intestinal Permeability: FITC-Dextran Serum Measurement and Transmission Electron Microscopy.. in Macrophage Migration Inhibitory Factor. 2020;:193-201.
doi:10.1007/978-1-4939-9936-1_17 .

Vujičić, Milica, Despotović, Sanja, Saksida, Tamara, Stojanović, Ivana D., Harris, James, Morand, Eric F., "The Effect of Macrophage Migration Inhibitory Factor on Intestinal Permeability: FITC-Dextran Serum Measurement and Transmission Electron Microscopy." in Macrophage Migration Inhibitory Factor (2020):193-201,
https://doi.org/10.1007/978-1-4939-9936-1_17 . .

TY  - THES
AU  - Koprivica, Ivan
PY  - 2020
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/4069
AB  - Dijabetes tipa 1 (DT1) je autoimunska bolest koja podrazumeva inflamaciju u pankreasu i smrt β ćelija, što kao posledicu ima smanjenje nivoa insulina, a povećanje nivoa glukoze u krvi. S obzirom na to da lek za DT1 još nije pronađen i da se obolele osobe oslanjaju na doživotni tretman insulinom, konstantni napori se ulažu u razvoj novih terapijskih pristupa. U tom cilju, u ovoj doktorskoj disertaciji je ispitivano dejstvo etil-piruvata, koji ima potvrđena antiinflamacijska svojstva, na razvoj DT1 u modelu bolesti na C57BL/6 miševima kojim je DT1 hemijski izazvan primenom višestrukih malih doza streptozotocina. Njegova profilaktička primena u navedenom modelu DT1 je dovela do smanjenja incidence bolesti, što je bilo praćeno manjom infiltracijom imunskih ćelija u pankreasna ostrvca i smanjenjem ekspresije primarnog ciljnog molekula etil-piruvata, HMGB1 (engl. High Mobility Group Box 1). Mehanizmi protektivnog dejstva etil-piruvata su obuhvatali stimulaciju regulatorne grane imunskog odgovora, tj. uvećanje udela tolerogenih dendritskih ćelija i regulatornih T (Treg) ćelija. Efekat etil-piruvata na Treg ćelije je podrazumevao njihovu uvećanu proliferaciju, diferencijaciju, migraciju i supresivnu funkciju i to prevashodno prema efektorskim T-bet+ T limfocitima. Pored uticaja na Treg ćelije u patološkim uslovima, etil-piruvat je ostvario stimulatorni efekat na ove ćelije i u homeostatskim uslovima, bilo da je primenjivan oralno ili intraperitonelano. Komplementarna in vitro istraživanja su pokazala da etil-piruvat ostvaruje svoj potencirajući uticaj na proliferaciju Treg ćelija, i to modulisanjem ćelijskog metabolizma putem stimulacije glikolize i inhibicije β-oksidacije masnih kiselina, dok je uticaj na Krebsov ciklus i oksidativnu fosforilaciju potpuno izostao. Rezultati ove doktorske disertacije ukazuju na značajan potencijal koji etil-piruvat ima u smirivanju inflamacije, ključnog efektorskog mehanizma tokom DT1, te da se njegova primena u lečenju DT1 može istraživati u budućim prekliničkim i kliničkim studijama.
AB  - Type 1 diabetes (T1D) is an autoimmune disease which triggers inflammation in the pancreas and the death of pancreatic β-cells, resulting in a decrease in insulin levels and increase of blood glucose levels. Since a cure for T1D still hasn’t been found and patients with T1D rely on a life-long insulin treatment, constant efforts are invested to develop new therapeutical approaches. To that end, this doctoral thesis was devoted to testing the effects of ethyl pyruvate, known to have anti-inflammatory properties, on the development of T1D, induced by multiple low-doses of streptozotocin, in C57BL/6 mice. Its prophylactic application in the aforementioned T1D model resulted in decreased disease incidence, accompanied by lessened immune cell infiltration into the pancreatic islets and reduced expression of the primary target molecule of ethyl pyruvate, HMGB1 (High Mobility Group Box 1). Ethyl pyruvate accomplished its protective influence by stimulating the regulatory arm of the immune response, namely by increasing the proportion of tolerogenic dendritic cells and regulatory T (Treg) cells. It also exerted its effects on Treg cells by increasing their proliferation, differentiation, migration and suppressive function, primarily towards effector T-bet+ T cells. Aside from its effects on Treg cells in pathological conditions, ethyl pyruvate stimulated Treg cells in homeostatic conditions, whether applied orally or intraperitoneally. Complementary in vitro experiments showed that ethyl pyruvate potentiates Treg cell proliferation, which is achieved through the modulation of cell metabolism, by stimulating glycolysis and suppressing fatty acid β-oxidation, while there is no effect on the citric acid cycle or oxidative phosphorylation. The results of this doctoral thesis indicate a notable potential of ethyl pyruvate to inhibit inflammation, a key part of T1D pathology, and that its application in T1D therapy can be further explored in preclinical and clinical studies.
PB  - Belgrade: University of Belgrade, Faculty of Biology
T2  - University of Belgrade, Faculty of Biology
T1  - Efekat primene etil-piruvata na razvoj  dijabetesa tipa 1 kod C57BL/6 miševa
T1  - Effects of ethyl pyruvate on the development of type 1 diabetes in C57BL/6 mice
SP  - 1
EP  - 119
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_4069
ER  - 

@phdthesis{
author = "Koprivica, Ivan",
year = "2020",
abstract = "Dijabetes tipa 1 (DT1) je autoimunska bolest koja podrazumeva inflamaciju u pankreasu i smrt β ćelija, što kao posledicu ima smanjenje nivoa insulina, a povećanje nivoa glukoze u krvi. S obzirom na to da lek za DT1 još nije pronađen i da se obolele osobe oslanjaju na doživotni tretman insulinom, konstantni napori se ulažu u razvoj novih terapijskih pristupa. U tom cilju, u ovoj doktorskoj disertaciji je ispitivano dejstvo etil-piruvata, koji ima potvrđena antiinflamacijska svojstva, na razvoj DT1 u modelu bolesti na C57BL/6 miševima kojim je DT1 hemijski izazvan primenom višestrukih malih doza streptozotocina. Njegova profilaktička primena u navedenom modelu DT1 je dovela do smanjenja incidence bolesti, što je bilo praćeno manjom infiltracijom imunskih ćelija u pankreasna ostrvca i smanjenjem ekspresije primarnog ciljnog molekula etil-piruvata, HMGB1 (engl. High Mobility Group Box 1). Mehanizmi protektivnog dejstva etil-piruvata su obuhvatali stimulaciju regulatorne grane imunskog odgovora, tj. uvećanje udela tolerogenih dendritskih ćelija i regulatornih T (Treg) ćelija. Efekat etil-piruvata na Treg ćelije je podrazumevao njihovu uvećanu proliferaciju, diferencijaciju, migraciju i supresivnu funkciju i to prevashodno prema efektorskim T-bet+ T limfocitima. Pored uticaja na Treg ćelije u patološkim uslovima, etil-piruvat je ostvario stimulatorni efekat na ove ćelije i u homeostatskim uslovima, bilo da je primenjivan oralno ili intraperitonelano. Komplementarna in vitro istraživanja su pokazala da etil-piruvat ostvaruje svoj potencirajući uticaj na proliferaciju Treg ćelija, i to modulisanjem ćelijskog metabolizma putem stimulacije glikolize i inhibicije β-oksidacije masnih kiselina, dok je uticaj na Krebsov ciklus i oksidativnu fosforilaciju potpuno izostao. Rezultati ove doktorske disertacije ukazuju na značajan potencijal koji etil-piruvat ima u smirivanju inflamacije, ključnog efektorskog mehanizma tokom DT1, te da se njegova primena u lečenju DT1 može istraživati u budućim prekliničkim i kliničkim studijama., Type 1 diabetes (T1D) is an autoimmune disease which triggers inflammation in the pancreas and the death of pancreatic β-cells, resulting in a decrease in insulin levels and increase of blood glucose levels. Since a cure for T1D still hasn’t been found and patients with T1D rely on a life-long insulin treatment, constant efforts are invested to develop new therapeutical approaches. To that end, this doctoral thesis was devoted to testing the effects of ethyl pyruvate, known to have anti-inflammatory properties, on the development of T1D, induced by multiple low-doses of streptozotocin, in C57BL/6 mice. Its prophylactic application in the aforementioned T1D model resulted in decreased disease incidence, accompanied by lessened immune cell infiltration into the pancreatic islets and reduced expression of the primary target molecule of ethyl pyruvate, HMGB1 (High Mobility Group Box 1). Ethyl pyruvate accomplished its protective influence by stimulating the regulatory arm of the immune response, namely by increasing the proportion of tolerogenic dendritic cells and regulatory T (Treg) cells. It also exerted its effects on Treg cells by increasing their proliferation, differentiation, migration and suppressive function, primarily towards effector T-bet+ T cells. Aside from its effects on Treg cells in pathological conditions, ethyl pyruvate stimulated Treg cells in homeostatic conditions, whether applied orally or intraperitoneally. Complementary in vitro experiments showed that ethyl pyruvate potentiates Treg cell proliferation, which is achieved through the modulation of cell metabolism, by stimulating glycolysis and suppressing fatty acid β-oxidation, while there is no effect on the citric acid cycle or oxidative phosphorylation. The results of this doctoral thesis indicate a notable potential of ethyl pyruvate to inhibit inflammation, a key part of T1D pathology, and that its application in T1D therapy can be further explored in preclinical and clinical studies.",
publisher = "Belgrade: University of Belgrade, Faculty of Biology",
journal = "University of Belgrade, Faculty of Biology",
title = "Efekat primene etil-piruvata na razvoj  dijabetesa tipa 1 kod C57BL/6 miševa, Effects of ethyl pyruvate on the development of type 1 diabetes in C57BL/6 mice",
pages = "1-119",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_4069"
}

Koprivica, I.. (2020). Efekat primene etil-piruvata na razvoj  dijabetesa tipa 1 kod C57BL/6 miševa. in University of Belgrade, Faculty of Biology
Belgrade: University of Belgrade, Faculty of Biology., 1-119.
https://hdl.handle.net/21.15107/rcub_ibiss_4069

Koprivica I. Efekat primene etil-piruvata na razvoj  dijabetesa tipa 1 kod C57BL/6 miševa. in University of Belgrade, Faculty of Biology. 2020;:1-119.
https://hdl.handle.net/21.15107/rcub_ibiss_4069 .

Koprivica, Ivan, "Efekat primene etil-piruvata na razvoj  dijabetesa tipa 1 kod C57BL/6 miševa" in University of Belgrade, Faculty of Biology (2020):1-119,
https://hdl.handle.net/21.15107/rcub_ibiss_4069 .

TY  - THES
AU  - Drača, Dijana
PY  - 2020
UR  - https://radar.ibiss.bg.ac.rs/123456789/3901
AB  - Tubulizini su sekundarni metaboliti miksobakterija koji svoju antitumorsku aktivnost ostvaruju narušavanjem organizacije deobnog vretena. U ovoj studiji ispitivan je antitumorski potencijal sintetskog analoga tubulizina, tubugi 1, in vitro i in vivo na modelu mišjeg i humanog melanoma. Tubugi 1 je pokazao selektivnost prema malignom fenotipu. U mišjim B16 ćelijama, tubugi 1 je indukovao atipičnu apoptozu bez eksternalizacije fosfatidilserina (PS), što je pripisano očuvanosti lipida membrane u uslovima intenzivnog oksidativnog stresa. Iako PS ima ključnu ulogu u uklanjaju apoptotskih ćelija, ovo se nije odrazilo na fagocitnu aktivnost makrofaga in vitro. Delotvornost eksperimentalnog agensa potvrdjena je in vivo. Smanjeni volumen tumora je, pored direktnog uticaja na maligne ćelije, rezultat i indukcije citotoksičnog fenotipa, kao i očuvane fagocitne sposobnosti makrofaga. Sa druge strane, kod A-375 ćelija tubugi 1 je indukovao mitotsku katastrofu, morfološki manifestovanu mikronukleacijama, a biohemijski – aktivacijom kaspaze 2 i nukleusnog faktora κB (NF-κB). Opisani fenomen bio je praćen intenziviranom, ali prolaznom autofagijom citoprotektivnog karaktera. Sa jenjavanjem autofagnog procesa, jačala je apoptoza praćena porastom proapoptotskog indeksa i aktivnosti kaspaze 3. Svi opisani događaji u potpunosti su korelirali sa dinamičnim promenama u signalnim putevima uključenim u ćelijsku deobu i smrt – mitogenom-aktivirane protein kinaze (MAPK) i fosfatidilinozitol 3-kinaze (PI3K/Akt). U celini, rezultati ove doktorske disertacije ukazaju na značajan antitumorski potencijal sintetskog derivata prirodnih tubulizina, tubugi 1, pokazan na modelu mišjeg i humanog melanoma.
AB  - Tubulysins are secondary metabolites of myxobacteria that exert their antitumor activity by disrupting the organization of the mitotic spindle. In this study, the antitumor potential of synthetic analog of tubulysins, tubugi 1, was tested in mouse and human melanoma model in vitro and in vivo. Tubugi 1 showed selectivity for the malignant phenotype. In murine B16 cells, tubugi 1 induced atypical apoptosis without phosphatidylserine (PS) externalization, which was attributed to membrane lipid preservation under conditions of intense oxidative stress. Although PS plays a key role in apoptotic cell removal, this did not affect macrophage phagocytic activity in vitro. The efficacy of the experimental agent was confirmed in vivo. In addition to its direct effect on malignant cells, reduced tumor volume is ascribed to established cytotoxic phenotype, as well as the preserved phagocytic ability of macrophages. On the other hand, in A-375 cells, tubugi 1 induced a mitotic catastrophe, manifested morphologically by micronuclei formation, and biochemically by activation of caspase 2 and the nuclear factor κB (NF-κB). The described phenomenon was accompanied by intense, but transient autophagy showing cytoprotective features. With the depletion of the autophagic process, apoptosis increased, followed by an increase in proapoptotic index and caspase 3 activity. All of the events described correlated completely with the dynamic changes in signaling pathways involved in cell division and death – mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K/Akt). Finally, the results of this doctoral dissertation pointed to the important antitumor potential of the synthetic derivative of natural tubulysins, tubugi 1, in the mouse and human melanoma model.
PB  - Belgrade: Faculty of Biology, University of Belgrade
T2  - Faculty of Biology, University of Belgrade
T1  - Molekulski mehanizmi delovanja antitumorskog agensa iz grupe sintetskih tubulizina, tubugi 1, na odabranim model sistemima melanoma
T1  - Molecular mechanisms of the action of antitumor agent from the synthetic tubulysins’ group, tubugi 1, on selected melanoma model systems
SP  - 1
EP  - 84
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_3901
ER  - 

@phdthesis{
author = "Drača, Dijana",
year = "2020",
abstract = "Tubulizini su sekundarni metaboliti miksobakterija koji svoju antitumorsku aktivnost ostvaruju narušavanjem organizacije deobnog vretena. U ovoj studiji ispitivan je antitumorski potencijal sintetskog analoga tubulizina, tubugi 1, in vitro i in vivo na modelu mišjeg i humanog melanoma. Tubugi 1 je pokazao selektivnost prema malignom fenotipu. U mišjim B16 ćelijama, tubugi 1 je indukovao atipičnu apoptozu bez eksternalizacije fosfatidilserina (PS), što je pripisano očuvanosti lipida membrane u uslovima intenzivnog oksidativnog stresa. Iako PS ima ključnu ulogu u uklanjaju apoptotskih ćelija, ovo se nije odrazilo na fagocitnu aktivnost makrofaga in vitro. Delotvornost eksperimentalnog agensa potvrdjena je in vivo. Smanjeni volumen tumora je, pored direktnog uticaja na maligne ćelije, rezultat i indukcije citotoksičnog fenotipa, kao i očuvane fagocitne sposobnosti makrofaga. Sa druge strane, kod A-375 ćelija tubugi 1 je indukovao mitotsku katastrofu, morfološki manifestovanu mikronukleacijama, a biohemijski – aktivacijom kaspaze 2 i nukleusnog faktora κB (NF-κB). Opisani fenomen bio je praćen intenziviranom, ali prolaznom autofagijom citoprotektivnog karaktera. Sa jenjavanjem autofagnog procesa, jačala je apoptoza praćena porastom proapoptotskog indeksa i aktivnosti kaspaze 3. Svi opisani događaji u potpunosti su korelirali sa dinamičnim promenama u signalnim putevima uključenim u ćelijsku deobu i smrt – mitogenom-aktivirane protein kinaze (MAPK) i fosfatidilinozitol 3-kinaze (PI3K/Akt). U celini, rezultati ove doktorske disertacije ukazaju na značajan antitumorski potencijal sintetskog derivata prirodnih tubulizina, tubugi 1, pokazan na modelu mišjeg i humanog melanoma., Tubulysins are secondary metabolites of myxobacteria that exert their antitumor activity by disrupting the organization of the mitotic spindle. In this study, the antitumor potential of synthetic analog of tubulysins, tubugi 1, was tested in mouse and human melanoma model in vitro and in vivo. Tubugi 1 showed selectivity for the malignant phenotype. In murine B16 cells, tubugi 1 induced atypical apoptosis without phosphatidylserine (PS) externalization, which was attributed to membrane lipid preservation under conditions of intense oxidative stress. Although PS plays a key role in apoptotic cell removal, this did not affect macrophage phagocytic activity in vitro. The efficacy of the experimental agent was confirmed in vivo. In addition to its direct effect on malignant cells, reduced tumor volume is ascribed to established cytotoxic phenotype, as well as the preserved phagocytic ability of macrophages. On the other hand, in A-375 cells, tubugi 1 induced a mitotic catastrophe, manifested morphologically by micronuclei formation, and biochemically by activation of caspase 2 and the nuclear factor κB (NF-κB). The described phenomenon was accompanied by intense, but transient autophagy showing cytoprotective features. With the depletion of the autophagic process, apoptosis increased, followed by an increase in proapoptotic index and caspase 3 activity. All of the events described correlated completely with the dynamic changes in signaling pathways involved in cell division and death – mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K/Akt). Finally, the results of this doctoral dissertation pointed to the important antitumor potential of the synthetic derivative of natural tubulysins, tubugi 1, in the mouse and human melanoma model.",
publisher = "Belgrade: Faculty of Biology, University of Belgrade",
journal = "Faculty of Biology, University of Belgrade",
title = "Molekulski mehanizmi delovanja antitumorskog agensa iz grupe sintetskih tubulizina, tubugi 1, na odabranim model sistemima melanoma, Molecular mechanisms of the action of antitumor agent from the synthetic tubulysins’ group, tubugi 1, on selected melanoma model systems",
pages = "1-84",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_3901"
}

Drača, D.. (2020). Molekulski mehanizmi delovanja antitumorskog agensa iz grupe sintetskih tubulizina, tubugi 1, na odabranim model sistemima melanoma. in Faculty of Biology, University of Belgrade
Belgrade: Faculty of Biology, University of Belgrade., 1-84.
https://hdl.handle.net/21.15107/rcub_ibiss_3901

Drača D. Molekulski mehanizmi delovanja antitumorskog agensa iz grupe sintetskih tubulizina, tubugi 1, na odabranim model sistemima melanoma. in Faculty of Biology, University of Belgrade. 2020;:1-84.
https://hdl.handle.net/21.15107/rcub_ibiss_3901 .

Drača, Dijana, "Molekulski mehanizmi delovanja antitumorskog agensa iz grupe sintetskih tubulizina, tubugi 1, na odabranim model sistemima melanoma" in Faculty of Biology, University of Belgrade (2020):1-84,
https://hdl.handle.net/21.15107/rcub_ibiss_3901 .

TY  - JOUR
AU  - Buzharevski, Antonio
AU  - Paskaš, Svetlana
AU  - Sárosi, Menyhárt-Botond
AU  - Laube, Markus
AU  - Lönnecke, Peter
AU  - Neumann, Wilma
AU  - Murganić, Blagoje
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
AU  - Pietzsch, Jens
AU  - Hey-Hawkins, Evamarie
PY  - 2020
UR  - http://www.ncbi.nlm.nih.gov/pubmed/32179835
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC7076013
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3640
AB  - Owing to the involvement of cyclooxygenase-2 (COX-2) in carcinogenesis, COX-2-selective inhibitors are increasingly studied for their potential cytotoxic properties. Moreover, the incorporation of carboranes in structures of established anti-inflammatory drugs can improve the potency and metabolic stability of the inhibitors. Herein, we report the synthesis of carborane-containing derivatives of rofecoxib that display remarkable cytotoxic or cytostatic activity in the micromolar range with excellent selectivity for melanoma and colon cancer cell lines over normal cells. Furthermore, it was shown that the carborane-modified derivatives of rofecoxib showed different modes of action that were dependent on the cell type.
T2  - Scientific Reports
T1  - Carboranyl Derivatives of Rofecoxib with Cytostatic Activity against Human Melanoma and Colon Cancer Cells.
IS  - 1
VL  - 10
DO  - 10.1038/s41598-020-59059-3
SP  - 4827
ER  - 

@article{
author = "Buzharevski, Antonio and Paskaš, Svetlana and Sárosi, Menyhárt-Botond and Laube, Markus and Lönnecke, Peter and Neumann, Wilma and Murganić, Blagoje and Mijatović, Sanja and Maksimović-Ivanić, Danijela and Pietzsch, Jens and Hey-Hawkins, Evamarie",
year = "2020",
abstract = "Owing to the involvement of cyclooxygenase-2 (COX-2) in carcinogenesis, COX-2-selective inhibitors are increasingly studied for their potential cytotoxic properties. Moreover, the incorporation of carboranes in structures of established anti-inflammatory drugs can improve the potency and metabolic stability of the inhibitors. Herein, we report the synthesis of carborane-containing derivatives of rofecoxib that display remarkable cytotoxic or cytostatic activity in the micromolar range with excellent selectivity for melanoma and colon cancer cell lines over normal cells. Furthermore, it was shown that the carborane-modified derivatives of rofecoxib showed different modes of action that were dependent on the cell type.",
journal = "Scientific Reports",
title = "Carboranyl Derivatives of Rofecoxib with Cytostatic Activity against Human Melanoma and Colon Cancer Cells.",
number = "1",
volume = "10",
doi = "10.1038/s41598-020-59059-3",
pages = "4827"
}

Buzharevski, A., Paskaš, S., Sárosi, M., Laube, M., Lönnecke, P., Neumann, W., Murganić, B., Mijatović, S., Maksimović-Ivanić, D., Pietzsch, J.,& Hey-Hawkins, E.. (2020). Carboranyl Derivatives of Rofecoxib with Cytostatic Activity against Human Melanoma and Colon Cancer Cells.. in Scientific Reports, 10(1), 4827.
https://doi.org/10.1038/s41598-020-59059-3

Buzharevski A, Paskaš S, Sárosi M, Laube M, Lönnecke P, Neumann W, Murganić B, Mijatović S, Maksimović-Ivanić D, Pietzsch J, Hey-Hawkins E. Carboranyl Derivatives of Rofecoxib with Cytostatic Activity against Human Melanoma and Colon Cancer Cells.. in Scientific Reports. 2020;10(1):4827.
doi:10.1038/s41598-020-59059-3 .

Buzharevski, Antonio, Paskaš, Svetlana, Sárosi, Menyhárt-Botond, Laube, Markus, Lönnecke, Peter, Neumann, Wilma, Murganić, Blagoje, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Pietzsch, Jens, Hey-Hawkins, Evamarie, "Carboranyl Derivatives of Rofecoxib with Cytostatic Activity against Human Melanoma and Colon Cancer Cells." in Scientific Reports, 10, no. 1 (2020):4827,
https://doi.org/10.1038/s41598-020-59059-3 . .

TY  - JOUR
AU  - Stošić-Grujičić, Stanislava
AU  - Saksida, Tamara
AU  - Miljković, Đorđe
AU  - Stojanović, Ivana D.
PY  - 2020
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3451
AB  - Pro-inflammatory nature of macrophage migration inhibitory factor (MIF) has been generally related to the
propagation of inflammatory and autoimmune diseases. But this molecule possesses many other peculiar
functions, unrelated to the immune system, among which is its supportive role in the post-translational modifications of insulin. In this way MIF enables proper insulin conformation within the pancreatic beta cell and its full activity. The inherent or acquired changes in MIF expression might therefore lead to different insulin processing and initiation of autoimmunity. The relation between MIF and insulin does not stop at this point; these two molecules continue to interact during pathological states characterized by inflammation and insulin resistance. In this context, MIF indirectly and negatively influences insulin action by boosting inflammatory environment and disabling target cells to respond to insulin. On the other side, insulin might interfere with MIF action as well, acting as an anti-inflammatory mediator. Therefore, the proper interaction between MIF and insulin is crucial for maintaining homeostasis, while anti-inflammatory therapies based on the systemic MIF blockage may disturb this balance. This review covers MIF-insulin relationship in the physiological and pathological conditions and discusses the approaches for MIF inhibition and their net effect specifically considering possible impact on insulin misfolding and the possible misinterpretation of previous results due to the discovery of MIF functional homolog D-dopachrome tautomerase.
PB  - Elsevier
T2  - Cytokine
T1  - MIF and insulin: Lifetime companions from common genesis to common pathogenesis
VL  - 125
DO  - 10.1016/j.cyto.2019.154792
SP  - 154792
ER  - 

@article{
author = "Stošić-Grujičić, Stanislava and Saksida, Tamara and Miljković, Đorđe and Stojanović, Ivana D.",
year = "2020",
abstract = "Pro-inflammatory nature of macrophage migration inhibitory factor (MIF) has been generally related to the
propagation of inflammatory and autoimmune diseases. But this molecule possesses many other peculiar
functions, unrelated to the immune system, among which is its supportive role in the post-translational modifications of insulin. In this way MIF enables proper insulin conformation within the pancreatic beta cell and its full activity. The inherent or acquired changes in MIF expression might therefore lead to different insulin processing and initiation of autoimmunity. The relation between MIF and insulin does not stop at this point; these two molecules continue to interact during pathological states characterized by inflammation and insulin resistance. In this context, MIF indirectly and negatively influences insulin action by boosting inflammatory environment and disabling target cells to respond to insulin. On the other side, insulin might interfere with MIF action as well, acting as an anti-inflammatory mediator. Therefore, the proper interaction between MIF and insulin is crucial for maintaining homeostasis, while anti-inflammatory therapies based on the systemic MIF blockage may disturb this balance. This review covers MIF-insulin relationship in the physiological and pathological conditions and discusses the approaches for MIF inhibition and their net effect specifically considering possible impact on insulin misfolding and the possible misinterpretation of previous results due to the discovery of MIF functional homolog D-dopachrome tautomerase.",
publisher = "Elsevier",
journal = "Cytokine",
title = "MIF and insulin: Lifetime companions from common genesis to common pathogenesis",
volume = "125",
doi = "10.1016/j.cyto.2019.154792",
pages = "154792"
}

Stošić-Grujičić, S., Saksida, T., Miljković, Đ.,& Stojanović, I. D.. (2020). MIF and insulin: Lifetime companions from common genesis to common pathogenesis. in Cytokine
Elsevier., 125, 154792.
https://doi.org/10.1016/j.cyto.2019.154792

Stošić-Grujičić S, Saksida T, Miljković Đ, Stojanović ID. MIF and insulin: Lifetime companions from common genesis to common pathogenesis. in Cytokine. 2020;125:154792.
doi:10.1016/j.cyto.2019.154792 .

Stošić-Grujičić, Stanislava, Saksida, Tamara, Miljković, Đorđe, Stojanović, Ivana D., "MIF and insulin: Lifetime companions from common genesis to common pathogenesis" in Cytokine, 125 (2020):154792,
https://doi.org/10.1016/j.cyto.2019.154792 . .

TY  - JOUR
AU  - Nikolovski, Neda
AU  - Jevtić, Bojan
AU  - Mansilla, M. José
AU  - Petković, Filip
AU  - Blaževski, Jana
AU  - Timotijević, Gordana
AU  - Navarro-Barriuso, Juan
AU  - Martinez-Caceres, Eva
AU  - Mostarica Stojković, Marija
AU  - Miljković, Đorđe
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S0171298518302201?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3265
AB  - Dendritic cells (DC) are responsible for the initiation and shaping of the adaptive immune response and are in the focus of autoimmunity research. We were interested in comparison of DC obtained from autoimmunity-prone Dark Agouti (DA) rats and autoimmunity-resistant Albino Oxford (AO) rats. DC were generated from bone marrow precursors and matured (mDC) by lipopolysaccharide. Tolerogenic DC (tolDC) obtained by vitamin D3 treatment were studied in parallel. Profile of cytokine production was different in AO and DA mDC and tolDC. Expression of MHC class II molecules and CD86 were higher in DA DC, while vitamin D3 reduced their expression in dendritic cells of both strains. Allogeneic proliferation of CD4+ T cells was reduced by AO tolDC, but not with DA tolDC in comparison to respective mDC. Finally, expression of various genes identified as differentially expressed in human mDC and tolDC was also analyzed in AO and DA DC. Again, AO and DA DC differed in the expression of the analyzed genes. To conclude, AO and DA DC differ in production of cytokines, expression of antigen presentation-related molecules and in regulation of CD4+ T proliferation. The difference is valuable for understanding the divergence of the strains in their susceptibility to autoimmunity.
T2  - Immunobiology
T1  - Comparison of dendritic cells obtained from autoimmunty-prone and resistant rats.
DO  - 10.1016/j.imbio.2019.01.001
ER  - 

@article{
author = "Nikolovski, Neda and Jevtić, Bojan and Mansilla, M. José and Petković, Filip and Blaževski, Jana and Timotijević, Gordana and Navarro-Barriuso, Juan and Martinez-Caceres, Eva and Mostarica Stojković, Marija and Miljković, Đorđe",
year = "2019",
abstract = "Dendritic cells (DC) are responsible for the initiation and shaping of the adaptive immune response and are in the focus of autoimmunity research. We were interested in comparison of DC obtained from autoimmunity-prone Dark Agouti (DA) rats and autoimmunity-resistant Albino Oxford (AO) rats. DC were generated from bone marrow precursors and matured (mDC) by lipopolysaccharide. Tolerogenic DC (tolDC) obtained by vitamin D3 treatment were studied in parallel. Profile of cytokine production was different in AO and DA mDC and tolDC. Expression of MHC class II molecules and CD86 were higher in DA DC, while vitamin D3 reduced their expression in dendritic cells of both strains. Allogeneic proliferation of CD4+ T cells was reduced by AO tolDC, but not with DA tolDC in comparison to respective mDC. Finally, expression of various genes identified as differentially expressed in human mDC and tolDC was also analyzed in AO and DA DC. Again, AO and DA DC differed in the expression of the analyzed genes. To conclude, AO and DA DC differ in production of cytokines, expression of antigen presentation-related molecules and in regulation of CD4+ T proliferation. The difference is valuable for understanding the divergence of the strains in their susceptibility to autoimmunity.",
journal = "Immunobiology",
title = "Comparison of dendritic cells obtained from autoimmunty-prone and resistant rats.",
doi = "10.1016/j.imbio.2019.01.001"
}

Nikolovski, N., Jevtić, B., Mansilla, M. J., Petković, F., Blaževski, J., Timotijević, G., Navarro-Barriuso, J., Martinez-Caceres, E., Mostarica Stojković, M.,& Miljković, Đ.. (2019). Comparison of dendritic cells obtained from autoimmunty-prone and resistant rats.. in Immunobiology.
https://doi.org/10.1016/j.imbio.2019.01.001

Nikolovski N, Jevtić B, Mansilla MJ, Petković F, Blaževski J, Timotijević G, Navarro-Barriuso J, Martinez-Caceres E, Mostarica Stojković M, Miljković Đ. Comparison of dendritic cells obtained from autoimmunty-prone and resistant rats.. in Immunobiology. 2019;.
doi:10.1016/j.imbio.2019.01.001 .

Nikolovski, Neda, Jevtić, Bojan, Mansilla, M. José, Petković, Filip, Blaževski, Jana, Timotijević, Gordana, Navarro-Barriuso, Juan, Martinez-Caceres, Eva, Mostarica Stojković, Marija, Miljković, Đorđe, "Comparison of dendritic cells obtained from autoimmunty-prone and resistant rats." in Immunobiology (2019),
https://doi.org/10.1016/j.imbio.2019.01.001 . .

TY  - JOUR
AU  - Koprivica, Ivan
AU  - Mićanović, Dragica
AU  - Saksida, Tamara
AU  - Cavalli, Eugenio
AU  - Auci, Dominick
AU  - Despotović, Sanja
AU  - Pejnović, Nada
AU  - Stošić-Grujičić, Stanislava
AU  - Nicoletti, Ferdinando
AU  - Stojanović, Ivana D.
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S0014299919306739?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3486
AB  - Type 1 diabetes (T1D) is a multifactorial autoimmune disease that develops as a consequence of macrophage- and T cell-dependent pancreatic β-cell death. Multiple approaches for induction of anti-inflammatory/regulatory mechanisms that would attenuate T1D have been utilized, with little or no beneficial effects. To achieve prolonged stimulation of regulatory immune cells, we orally introduced microparticles (MPs) loaded with all-trans retinoic acid (ATRA) and transforming growth factor-β (TGF-β) to C57BL/6 mice treated with multiple low doses of streptozotocin (MLDS) for T1D induction. Disease incidence was significantly lower in ATRA/TGF-β MPs-treated mice, as was the degree of immune cell infiltration into the pancreatic islets. In Peyer's patches (PP), ATRA/TGF-β MPs up-regulated tolerogenic dendritic cells (tolDCs) (CD11c+CD11b-CD103+), while the proportion of mature dendritic cells was not altered. This was accompanied by reduced Th1 and Th17 proportions and up-regulation of regulatory T cells (Tregs - CD4+CD25highFoxP3+). The immune cell composition in the pancreatic lymph nodes was similar to PP. Further, the proportion of effector Tbet+CD25med cells was decreased, while the proportion of Tbet+ Treg cells that specifically inhibit Th1 response was increased. Moreover, ATRA/TGF-β MPs treatment resulted in increased Treg proliferation and frequency of CTLA-4+PD1+ and CD39+IL-10+ Tregs, suggestive of their higher suppressive capacity. Reduced pancreatic infiltration may have been a consequence of lower cell capacity for matrix degradation. In conclusion, oral application of ATRA/TGF-β MPs ameliorated T1D through potentiation of tolDCs and Tregs, inhibition of Th1 response and prevention of the immune cell entrance into the islets.
T2  - European Journal of Pharmacology
T1  - Orally delivered all-trans-retinoic acid- and transforming growth factor-β-loaded microparticles ameliorate type 1 diabetes in mice
VL  - 864
DO  - 10.1016/j.ejphar.2019.172721
SP  - 172721
ER  - 

@article{
author = "Koprivica, Ivan and Mićanović, Dragica and Saksida, Tamara and Cavalli, Eugenio and Auci, Dominick and Despotović, Sanja and Pejnović, Nada and Stošić-Grujičić, Stanislava and Nicoletti, Ferdinando and Stojanović, Ivana D.",
year = "2019",
abstract = "Type 1 diabetes (T1D) is a multifactorial autoimmune disease that develops as a consequence of macrophage- and T cell-dependent pancreatic β-cell death. Multiple approaches for induction of anti-inflammatory/regulatory mechanisms that would attenuate T1D have been utilized, with little or no beneficial effects. To achieve prolonged stimulation of regulatory immune cells, we orally introduced microparticles (MPs) loaded with all-trans retinoic acid (ATRA) and transforming growth factor-β (TGF-β) to C57BL/6 mice treated with multiple low doses of streptozotocin (MLDS) for T1D induction. Disease incidence was significantly lower in ATRA/TGF-β MPs-treated mice, as was the degree of immune cell infiltration into the pancreatic islets. In Peyer's patches (PP), ATRA/TGF-β MPs up-regulated tolerogenic dendritic cells (tolDCs) (CD11c+CD11b-CD103+), while the proportion of mature dendritic cells was not altered. This was accompanied by reduced Th1 and Th17 proportions and up-regulation of regulatory T cells (Tregs - CD4+CD25highFoxP3+). The immune cell composition in the pancreatic lymph nodes was similar to PP. Further, the proportion of effector Tbet+CD25med cells was decreased, while the proportion of Tbet+ Treg cells that specifically inhibit Th1 response was increased. Moreover, ATRA/TGF-β MPs treatment resulted in increased Treg proliferation and frequency of CTLA-4+PD1+ and CD39+IL-10+ Tregs, suggestive of their higher suppressive capacity. Reduced pancreatic infiltration may have been a consequence of lower cell capacity for matrix degradation. In conclusion, oral application of ATRA/TGF-β MPs ameliorated T1D through potentiation of tolDCs and Tregs, inhibition of Th1 response and prevention of the immune cell entrance into the islets.",
journal = "European Journal of Pharmacology",
title = "Orally delivered all-trans-retinoic acid- and transforming growth factor-β-loaded microparticles ameliorate type 1 diabetes in mice",
volume = "864",
doi = "10.1016/j.ejphar.2019.172721",
pages = "172721"
}

Koprivica, I., Mićanović, D., Saksida, T., Cavalli, E., Auci, D., Despotović, S., Pejnović, N., Stošić-Grujičić, S., Nicoletti, F.,& Stojanović, I. D.. (2019). Orally delivered all-trans-retinoic acid- and transforming growth factor-β-loaded microparticles ameliorate type 1 diabetes in mice. in European Journal of Pharmacology, 864, 172721.
https://doi.org/10.1016/j.ejphar.2019.172721

Koprivica I, Mićanović D, Saksida T, Cavalli E, Auci D, Despotović S, Pejnović N, Stošić-Grujičić S, Nicoletti F, Stojanović ID. Orally delivered all-trans-retinoic acid- and transforming growth factor-β-loaded microparticles ameliorate type 1 diabetes in mice. in European Journal of Pharmacology. 2019;864:172721.
doi:10.1016/j.ejphar.2019.172721 .

Koprivica, Ivan, Mićanović, Dragica, Saksida, Tamara, Cavalli, Eugenio, Auci, Dominick, Despotović, Sanja, Pejnović, Nada, Stošić-Grujičić, Stanislava, Nicoletti, Ferdinando, Stojanović, Ivana D., "Orally delivered all-trans-retinoic acid- and transforming growth factor-β-loaded microparticles ameliorate type 1 diabetes in mice" in European Journal of Pharmacology, 864 (2019):172721,
https://doi.org/10.1016/j.ejphar.2019.172721 . .

TY  - JOUR
AU  - Koprivica, Ivan
AU  - Vujičić, Milica
AU  - Mićanović, Dragica
AU  - Saksida, Tamara
AU  - Stojanović, Ivana D.
PY  - 2019
UR  - https://www.frontiersin.org/article/10.3389/fimmu.2018.03130/full
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC6335294
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3249
AB  - Type 1 diabetes (T1D) is an autoimmune disease in which a strong inflammatory response causes the death of insulin-producing pancreatic β-cells, while inefficient regulatory mechanisms allow that response to become chronic. Ethyl pyruvate (EP), a stable pyruvate derivate and certified inhibitor of an alarmin-high mobility group box 1 (HMGB1), exerts anti-oxidant and anti-inflammatory properties in animal models of rheumatoid arthritis and encephalomyelitis. To test its therapeutic potential in T1D, EP was administered intraperitoneally to C57BL/6 mice with multiple low-dose streptozotocin (MLDS)-induced T1D. EP treatment decreased T1D incidence, reduced the infiltration of cells into the pancreatic islets and preserved β-cell function. Apart from reducing HMGB1 expression, EP treatment successfully interfered with the inflammatory response within the local pancreatic lymph nodes and in the pancreas. Its effect was restricted to boosting the regulatory arm of the immune response through up-regulation of tolerogenic dendritic cells (CD11c+CD11b-CD103+) within the pancreatic infiltrates and through the enhancement of regulatory T cell (Treg) levels (CD4+CD25highFoxP3+). These EP-stimulated Treg displayed enhanced suppressive capacity reflected in increased levels of CTLA-4, secreted TGF-β, and IL-10 and in the more efficient inhibition of effector T cell proliferation compared to Treg from diabetic animals. Higher levels of Treg were a result of increased differentiation and proliferation (Ki67+ cells), but also of the heightened potency for migration due to increased expression of adhesion molecules (CD11a and CD62L) and CXCR3 chemokine receptor. Treg isolated from EP-treated mice had the activated phenotype and T-bet expression more frequently, suggesting that they readily suppressed IFN-γ-producing cells. The effect of EP on Treg was also reproduced in vitro. Overall, our results show that EP treatment reduced T1D incidence in C57BL/6 mice predominantly by enhancing Treg differentiation, proliferation, their suppressive capacity, and recruitment into the pancreas.
T2  - Frontiers in Immunology
T1  - Ethyl Pyruvate Stimulates Regulatory T Cells and Ameliorates Type 1 Diabetes Development in Mice.
VL  - 9
DO  - 10.3389/fimmu.2018.03130
SP  - 3130
ER  - 

@article{
author = "Koprivica, Ivan and Vujičić, Milica and Mićanović, Dragica and Saksida, Tamara and Stojanović, Ivana D.",
year = "2019",
abstract = "Type 1 diabetes (T1D) is an autoimmune disease in which a strong inflammatory response causes the death of insulin-producing pancreatic β-cells, while inefficient regulatory mechanisms allow that response to become chronic. Ethyl pyruvate (EP), a stable pyruvate derivate and certified inhibitor of an alarmin-high mobility group box 1 (HMGB1), exerts anti-oxidant and anti-inflammatory properties in animal models of rheumatoid arthritis and encephalomyelitis. To test its therapeutic potential in T1D, EP was administered intraperitoneally to C57BL/6 mice with multiple low-dose streptozotocin (MLDS)-induced T1D. EP treatment decreased T1D incidence, reduced the infiltration of cells into the pancreatic islets and preserved β-cell function. Apart from reducing HMGB1 expression, EP treatment successfully interfered with the inflammatory response within the local pancreatic lymph nodes and in the pancreas. Its effect was restricted to boosting the regulatory arm of the immune response through up-regulation of tolerogenic dendritic cells (CD11c+CD11b-CD103+) within the pancreatic infiltrates and through the enhancement of regulatory T cell (Treg) levels (CD4+CD25highFoxP3+). These EP-stimulated Treg displayed enhanced suppressive capacity reflected in increased levels of CTLA-4, secreted TGF-β, and IL-10 and in the more efficient inhibition of effector T cell proliferation compared to Treg from diabetic animals. Higher levels of Treg were a result of increased differentiation and proliferation (Ki67+ cells), but also of the heightened potency for migration due to increased expression of adhesion molecules (CD11a and CD62L) and CXCR3 chemokine receptor. Treg isolated from EP-treated mice had the activated phenotype and T-bet expression more frequently, suggesting that they readily suppressed IFN-γ-producing cells. The effect of EP on Treg was also reproduced in vitro. Overall, our results show that EP treatment reduced T1D incidence in C57BL/6 mice predominantly by enhancing Treg differentiation, proliferation, their suppressive capacity, and recruitment into the pancreas.",
journal = "Frontiers in Immunology",
title = "Ethyl Pyruvate Stimulates Regulatory T Cells and Ameliorates Type 1 Diabetes Development in Mice.",
volume = "9",
doi = "10.3389/fimmu.2018.03130",
pages = "3130"
}

Koprivica, I., Vujičić, M., Mićanović, D., Saksida, T.,& Stojanović, I. D.. (2019). Ethyl Pyruvate Stimulates Regulatory T Cells and Ameliorates Type 1 Diabetes Development in Mice.. in Frontiers in Immunology, 9, 3130.
https://doi.org/10.3389/fimmu.2018.03130

Koprivica I, Vujičić M, Mićanović D, Saksida T, Stojanović ID. Ethyl Pyruvate Stimulates Regulatory T Cells and Ameliorates Type 1 Diabetes Development in Mice.. in Frontiers in Immunology. 2019;9:3130.
doi:10.3389/fimmu.2018.03130 .

Koprivica, Ivan, Vujičić, Milica, Mićanović, Dragica, Saksida, Tamara, Stojanović, Ivana D., "Ethyl Pyruvate Stimulates Regulatory T Cells and Ameliorates Type 1 Diabetes Development in Mice." in Frontiers in Immunology, 9 (2019):3130,
https://doi.org/10.3389/fimmu.2018.03130 . .

TY  - THES
AU  - Nikolovski, Neda
PY  - 2019
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3425
AB  - Multipla skleroza (MS) je hronična, inflamacijska, demijelinizirajuća bolest centralnog nervnog sistema (CNS-a). Autoimunski odgovor usmeren protiv CNS-a je bitan element patogeneze MS-e. Eksperimentalni autoimunski encefalomijelitis (EAE) predstavlja životinjski model MS-e pomoću kog se istražuju patogenetski mehanizmi ove bolesti. Glavne ćelije koje učestvuju u pokretanju autoimunskog odgovora usmerenog protiv CNS-a su antigen prezentujuće ćelije (APĆ) koje aktiviraju naivne CD4+ T-ćelije specifične za antigene CNS-a. Ove CD4+ T-ćelije se potom diferenciraju u efektorske Th1 (engl. T helper cells – Th ćelije) koje imaju sposobnost produkcije interferona γ (IFN-γ) i Th17 koje produkuju interleukin 17 (IL-17). Prolaskom kroz-krvno-moždanu barijeru, Th1 i Th17 ćelije dolaze u CNS gde ih reaktiviraju rezidentne APĆ, te one sva.ojim produktima privlače druge imunske ćelije u CNS, što sve dovodi do inflamacije koja vodi oštećenju tkiva CNS-a. Patogenezi bolesti doprinose i rezidentne ćelije CNS-a kao što su astrociti i mikroglija. Etil-piruvat (EP) je lipofilni estar pirogrožđane kiseline koji poseduje antioksidativna i antiinflamacijska svojstva. U ovoj studiji je ispitivan antiencefalitogeni efekat EP-a na tok EAE-a i ćelije ukjučene u patogenezu EAE-a. Takođe, ispitivan je i njegov in vitro i in vivo tolerogeni uticaj na dendritske ćelije (DĆ). Rezultati su pokazali da EP ostvaruje terapijsko dejstvo na EAE kada se daje pacovima svakodnevno, počev od pojave prvih kliničkih simptoma bolesti sve do njihovog inicijalnog oporavka. Svoj antiencefalitogeni efekat EP je ispoljio sprečavanjem infiltracije imunskih ćelija u CNS, inhibicijom produkcije IL-17 od strane CD4+ T-limfocita u kičmenoj moždini, čime je sprečio zapaljensku reakciju u CNS-u. EP je doveo i do redukcije broja reaktivnih makrofaga i ćelija mikroglije, kao i do inhibicije reaktivnosti astrocita. Takođe, sprečio je i oštećenje neurona. Jedan od mehanizama kojim je EP ostvario svoje dejstvo je inhibicija HMGB1 (grupa proteina visoke mobilnosti 1 (engl. High-mobility group box 1) u reaktivnim makrofagima/mikrogliji. Da EP ima i druge efekte na APĆ pokazali su rezultati na makrofagima, in vitro. EP je redukovao produkciju proinflamacijskih citokina od strane makrofaga i ekspresiju molekula bitnih za prezentaciju antigena na ovim ćelijama. Zatim, istraživanje je prošireno na DĆ kao profesionalne APĆ. Rezultati su pokazali da EP vrši tolerogeni uticaj na DĆ poreklom iz kostne srži miševa. Naime, tretman DĆ-a in vitro EP-om inhibira njihovu sposobnost efikasne prezentacije antigena, aktivacije T ćelija u alogenoj reakciji i produkcije proinflamacijskih citokina. Molekulski mehanizmi kojim EP ostvaruje svoje dejstvo na mišje DĆ, uključuju stimulaciju signalnog molekula nuklearnog faktora povezanog sa eritrocitima 2 (engl. Nuclear Factor Erythroid 2–related Factor 2-Nrf2) i enzima hem oksigenaze 1 (HO-1) i NQO1 (engl. NADPH-quinone oxidoreductase 1), kao i inhibiciju regulatornog proteina transkripcije nuklearnog faktora κB (NF-κB). EP-om tretirane DĆ ispoljavaju efekte in vivo inhibiranjem imunskog odgovora indukovanog kompletnim Frojndovim adjuvansom u miševa. Konačno, tolerogeno dejstvo EP-a pokazano je i na DĆ-ma diferenciranim iz monocita ljudi (engl. Monocyte derived Dendritic Cells - MoDĆ) dobrovoljnih davalaca krvi i pacijenata obolelih od MS-e. Iz rezultata ove doktorske disertacije proizilazi da je EP efikasno imunomodulacijsko jedinjenje koje inhibira EAE, kao i da je efikasno tolerogeno jedinjenje koje usmerava DĆ ka imunosupresivnom fenotipu. Samim tim, zaključuje se da EP ima potencijal da bude primenjen u terapiji MS-e. Primena EP bi mogla biti direktna ili u pripremi tolerogenih DĆ za ćelijsku imunoterapiju. Buduće predkliničke i kliničke studije bi trebalo da budu usmerene na istraživanje mogućnosti primene EP u terapiji MS-e, ali i drugih autoimunskih i hroničnih inflamacijskih bolesti. Ključne reči: eksperimentalni autoimunski encefalomijelitis, multipla skleroza, etil-piruvat, tolerogene dendritske ćelije Naučna oblast: Biologija Uža naučna oblast: Imunologija UDK broj: Anti-encephalitogenic mechanisms of ethyl pyruvate in experimental autoimmune encephalomyelitis Abstract Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) with proposed autoimmune pathogenesis. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is widely used to investigate pathogenetic mechanisms of the disease. Antigen presenting cells (APC) are major cells that are involved in the initiation of the autoimmune response against the CNS by activating CNS-specific naive CD4+ T cells. Consequently, these CD4+ T cells differentiate into effector T helper cells 1 (Th1) that produce interferon γ (IFN-γ) and Th17 cells that produce interleukin 17 (IL-17). Passing through the blood brain barrier, Th1 and Th17 cells arrive in the CNS where they become reactivated by the resident APC. Afterwards, other immune cells infiltrate the CNS, thus causing inflammation and tissue damage. The resident cells of the CNS, such as astrocytes and microglia, also contribute to the disease pathogenesis. Ethyl pyruvate (EP) is a lipophilic ester of pyruvic acid that possesses anti-oxidative and anti-inflammatory properties. The anti-encephalitogenic effect of EP in EAE and on cells of the CNS involved in the disease pathogenesis, were investigated in this study. Also, its in vitro and in vivo tolerogenic effect on dendritic cells (DC) was studied. Results showed that EP had a therapeutic effect on EAE when applied to the rats once a day, starting from the first clinical symptoms until their initial recovery. EP prevented immune cells infiltration into the CNS and inhibited T cell production of IL-17 in the spinal cord. Thus, EP restrained the inflammatory reaction in the CNS and therefore exerted its anti-encephalitogenic effect. Furthermore, treatment with EP led to the reduction of macrophages and microglia cell number, inhibition of astrocyte activity, as well as neuron destruction. Inhibition of HMGB1 (High-Mobility Group Box 1) molecule in activated macrophages/microglia was one of the mechanisms of the EP effects in the CNS. Moreover, in vitro treatment of stimulated macrophages with EP showed that EP had also an impact on APC. Treatment with EP led to reduced production of pro-inflammatory cytokines by macrophages as well as to downregulation of the expression of molecules relevant for antigen presentation. Furthermore, EP had a tolerogenic effect on the major APC, i.e. DC. Mice bone marrow derived DC were investigated. In vitro treatment of DC with EP inhibited their ability to efficiently present antigens, to activate T cells in allogeneic reaction, and to produce pro-inflammatory cytokines. Molecular mechanisms involved in the tolerogenic effects of EP on mice DC included stimulation of nuclear factor erythroid 2–related factor 2 (Nrf2) signaling, increase of heme oxygenase-1 (HO1) and NADPH-quinone oxidoreductase 1 (NQO1) expression, and inhibition of nuclear factor κB (NF-κB) transcription factor activation. Also, EP-treated DC inhibited immune response in vivo induced with complete Freund’s adjuvant in mice. Finally, the tolerogenic effects of EP were demonstrated in human monocyte derived DC (MoDC) obtained from healthy individuals and MS patients. Results of this doctoral thesis show that EP ameliorates EAE and that is also an effective tolerogenic agent that shifts DC towards immune-suppressing phenotype. Thereby, EP has the potential to be applied in MS therapy. Its application could be direct or through generation of tolerogenic DC as a mean of cell-based immunotherapy. Future preclinical and clinical studies should be focused towards investigating the possible application of EP in MS therapy, as well as in other autoimmune and chronic inflammatory diseases.
AB  - Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) with proposed autoimmune pathogenesis. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is widely used to investigate pathogenetic mechanisms of the disease. Antigen presenting cells (APC) are major cells that are involved in the initiation of the autoimmune response against the CNS by activating CNS-specific naive CD4+ T cells. Consequently, these CD4+ T cells differentiate into effector T helper cells 1 (Th1) that produce interferon γ (IFN-γ) and Th17 cells that produce interleukin 17 (IL-17). Passing through the blood brain barrier, Th1 and Th17 cells arrive in the CNS where they become reactivated by the resident APC. Afterwards, other immune cells infiltrate the CNS, thus causing inflammation and tissue damage. The resident cells of the CNS, such as astrocytes and microglia, also contribute to the disease pathogenesis. Ethyl pyruvate (EP) is a lipophilic ester of pyruvic acid that possesses anti-oxidative and anti-inflammatory properties. The anti-encephalitogenic effect of EP in EAE and on cells of the CNS involved in the disease pathogenesis, were investigated in this study. Also, its in vitro and in vivo tolerogenic effect on dendritic cells (DC) was studied. Results showed that EP had a therapeutic effect on EAE when applied to the rats once a day, starting from the first clinical symptoms until their initial recovery. EP prevented immune cells infiltration into the CNS and inhibited T cell production of IL-17 in the spinal cord. Thus, EP restrained the inflammatory reaction in the CNS and therefore exerted its anti-encephalitogenic effect. Furthermore, treatment with EP led to the reduction of macrophages and microglia cell number, inhibition of astrocyte activity, as well as neuron destruction. Inhibition of HMGB1 (High-Mobility Group Box 1) molecule in activated macrophages/microglia was one of the mechanisms of the EP effects in the CNS. Moreover, in vitro treatment of stimulated macrophages with EP showed that EP had also an impact on APC. Treatment with EP led to reduced production of pro-inflammatory cytokines by macrophages as well as to downregulation of the expression of molecules relevant for antigen presentation. Furthermore, EP had a tolerogenic effect on the major APC, i.e. DC. Mice bone marrow derived DC were investigated. In vitro treatment of DC with EP inhibited their ability to efficiently present antigens, to activate T cells in allogeneic reaction, and to produce pro-inflammatory cytokines. Molecular mechanisms involved in the tolerogenic effects of EP on mice DC included stimulation of nuclear factor erythroid 2–related factor 2 (Nrf2) signaling, increase of heme oxygenase-1 (HO1) and NADPH-quinone oxidoreductase 1 (NQO1) expression, and inhibition of nuclear factor κB (NF-κB) transcription factor activation. Also, EP-treated DC inhibited immune response in vivo induced with complete Freund’s adjuvant in mice. Finally, the tolerogenic effects of EP were demonstrated in human monocyte derived DC (MoDC) obtained from healthy individuals and MS patients. Results of this doctoral thesis show that EP ameliorates EAE and that is also an effective tolerogenic agent that shifts DC towards immune-suppressing phenotype. Thereby, EP has the potential to be applied in MS therapy. Its application could be direct or through generation of tolerogenic DC as a mean of cell-based immunotherapy. Future preclinical and clinical studies should be focused towards investigating the possible application of EP in MS therapy, as well as in other autoimmune and chronic inflammatory diseases.
PB  - Belgrade: University of Belgrade, Faculty of Biology
T2  - University of Belgrade, Faculty of Biology
T1  - Mehanizmi antiencefalitogenog dejstva etil-piruvata u eksperimentalnom autoimunskom encefalomijelitisu
T1  - Anti-encephalitogenic mechanisms of ethyl pyruvate in experimental autoimmune encephalomyelitis
SP  - 1
EP  - 122
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_3425
ER  - 

@phdthesis{
author = "Nikolovski, Neda",
year = "2019",
abstract = "Multipla skleroza (MS) je hronična, inflamacijska, demijelinizirajuća bolest centralnog nervnog sistema (CNS-a). Autoimunski odgovor usmeren protiv CNS-a je bitan element patogeneze MS-e. Eksperimentalni autoimunski encefalomijelitis (EAE) predstavlja životinjski model MS-e pomoću kog se istražuju patogenetski mehanizmi ove bolesti. Glavne ćelije koje učestvuju u pokretanju autoimunskog odgovora usmerenog protiv CNS-a su antigen prezentujuće ćelije (APĆ) koje aktiviraju naivne CD4+ T-ćelije specifične za antigene CNS-a. Ove CD4+ T-ćelije se potom diferenciraju u efektorske Th1 (engl. T helper cells – Th ćelije) koje imaju sposobnost produkcije interferona γ (IFN-γ) i Th17 koje produkuju interleukin 17 (IL-17). Prolaskom kroz-krvno-moždanu barijeru, Th1 i Th17 ćelije dolaze u CNS gde ih reaktiviraju rezidentne APĆ, te one sva.ojim produktima privlače druge imunske ćelije u CNS, što sve dovodi do inflamacije koja vodi oštećenju tkiva CNS-a. Patogenezi bolesti doprinose i rezidentne ćelije CNS-a kao što su astrociti i mikroglija. Etil-piruvat (EP) je lipofilni estar pirogrožđane kiseline koji poseduje antioksidativna i antiinflamacijska svojstva. U ovoj studiji je ispitivan antiencefalitogeni efekat EP-a na tok EAE-a i ćelije ukjučene u patogenezu EAE-a. Takođe, ispitivan je i njegov in vitro i in vivo tolerogeni uticaj na dendritske ćelije (DĆ). Rezultati su pokazali da EP ostvaruje terapijsko dejstvo na EAE kada se daje pacovima svakodnevno, počev od pojave prvih kliničkih simptoma bolesti sve do njihovog inicijalnog oporavka. Svoj antiencefalitogeni efekat EP je ispoljio sprečavanjem infiltracije imunskih ćelija u CNS, inhibicijom produkcije IL-17 od strane CD4+ T-limfocita u kičmenoj moždini, čime je sprečio zapaljensku reakciju u CNS-u. EP je doveo i do redukcije broja reaktivnih makrofaga i ćelija mikroglije, kao i do inhibicije reaktivnosti astrocita. Takođe, sprečio je i oštećenje neurona. Jedan od mehanizama kojim je EP ostvario svoje dejstvo je inhibicija HMGB1 (grupa proteina visoke mobilnosti 1 (engl. High-mobility group box 1) u reaktivnim makrofagima/mikrogliji. Da EP ima i druge efekte na APĆ pokazali su rezultati na makrofagima, in vitro. EP je redukovao produkciju proinflamacijskih citokina od strane makrofaga i ekspresiju molekula bitnih za prezentaciju antigena na ovim ćelijama. Zatim, istraživanje je prošireno na DĆ kao profesionalne APĆ. Rezultati su pokazali da EP vrši tolerogeni uticaj na DĆ poreklom iz kostne srži miševa. Naime, tretman DĆ-a in vitro EP-om inhibira njihovu sposobnost efikasne prezentacije antigena, aktivacije T ćelija u alogenoj reakciji i produkcije proinflamacijskih citokina. Molekulski mehanizmi kojim EP ostvaruje svoje dejstvo na mišje DĆ, uključuju stimulaciju signalnog molekula nuklearnog faktora povezanog sa eritrocitima 2 (engl. Nuclear Factor Erythroid 2–related Factor 2-Nrf2) i enzima hem oksigenaze 1 (HO-1) i NQO1 (engl. NADPH-quinone oxidoreductase 1), kao i inhibiciju regulatornog proteina transkripcije nuklearnog faktora κB (NF-κB). EP-om tretirane DĆ ispoljavaju efekte in vivo inhibiranjem imunskog odgovora indukovanog kompletnim Frojndovim adjuvansom u miševa. Konačno, tolerogeno dejstvo EP-a pokazano je i na DĆ-ma diferenciranim iz monocita ljudi (engl. Monocyte derived Dendritic Cells - MoDĆ) dobrovoljnih davalaca krvi i pacijenata obolelih od MS-e. Iz rezultata ove doktorske disertacije proizilazi da je EP efikasno imunomodulacijsko jedinjenje koje inhibira EAE, kao i da je efikasno tolerogeno jedinjenje koje usmerava DĆ ka imunosupresivnom fenotipu. Samim tim, zaključuje se da EP ima potencijal da bude primenjen u terapiji MS-e. Primena EP bi mogla biti direktna ili u pripremi tolerogenih DĆ za ćelijsku imunoterapiju. Buduće predkliničke i kliničke studije bi trebalo da budu usmerene na istraživanje mogućnosti primene EP u terapiji MS-e, ali i drugih autoimunskih i hroničnih inflamacijskih bolesti. Ključne reči: eksperimentalni autoimunski encefalomijelitis, multipla skleroza, etil-piruvat, tolerogene dendritske ćelije Naučna oblast: Biologija Uža naučna oblast: Imunologija UDK broj: Anti-encephalitogenic mechanisms of ethyl pyruvate in experimental autoimmune encephalomyelitis Abstract Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) with proposed autoimmune pathogenesis. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is widely used to investigate pathogenetic mechanisms of the disease. Antigen presenting cells (APC) are major cells that are involved in the initiation of the autoimmune response against the CNS by activating CNS-specific naive CD4+ T cells. Consequently, these CD4+ T cells differentiate into effector T helper cells 1 (Th1) that produce interferon γ (IFN-γ) and Th17 cells that produce interleukin 17 (IL-17). Passing through the blood brain barrier, Th1 and Th17 cells arrive in the CNS where they become reactivated by the resident APC. Afterwards, other immune cells infiltrate the CNS, thus causing inflammation and tissue damage. The resident cells of the CNS, such as astrocytes and microglia, also contribute to the disease pathogenesis. Ethyl pyruvate (EP) is a lipophilic ester of pyruvic acid that possesses anti-oxidative and anti-inflammatory properties. The anti-encephalitogenic effect of EP in EAE and on cells of the CNS involved in the disease pathogenesis, were investigated in this study. Also, its in vitro and in vivo tolerogenic effect on dendritic cells (DC) was studied. Results showed that EP had a therapeutic effect on EAE when applied to the rats once a day, starting from the first clinical symptoms until their initial recovery. EP prevented immune cells infiltration into the CNS and inhibited T cell production of IL-17 in the spinal cord. Thus, EP restrained the inflammatory reaction in the CNS and therefore exerted its anti-encephalitogenic effect. Furthermore, treatment with EP led to the reduction of macrophages and microglia cell number, inhibition of astrocyte activity, as well as neuron destruction. Inhibition of HMGB1 (High-Mobility Group Box 1) molecule in activated macrophages/microglia was one of the mechanisms of the EP effects in the CNS. Moreover, in vitro treatment of stimulated macrophages with EP showed that EP had also an impact on APC. Treatment with EP led to reduced production of pro-inflammatory cytokines by macrophages as well as to downregulation of the expression of molecules relevant for antigen presentation. Furthermore, EP had a tolerogenic effect on the major APC, i.e. DC. Mice bone marrow derived DC were investigated. In vitro treatment of DC with EP inhibited their ability to efficiently present antigens, to activate T cells in allogeneic reaction, and to produce pro-inflammatory cytokines. Molecular mechanisms involved in the tolerogenic effects of EP on mice DC included stimulation of nuclear factor erythroid 2–related factor 2 (Nrf2) signaling, increase of heme oxygenase-1 (HO1) and NADPH-quinone oxidoreductase 1 (NQO1) expression, and inhibition of nuclear factor κB (NF-κB) transcription factor activation. Also, EP-treated DC inhibited immune response in vivo induced with complete Freund’s adjuvant in mice. Finally, the tolerogenic effects of EP were demonstrated in human monocyte derived DC (MoDC) obtained from healthy individuals and MS patients. Results of this doctoral thesis show that EP ameliorates EAE and that is also an effective tolerogenic agent that shifts DC towards immune-suppressing phenotype. Thereby, EP has the potential to be applied in MS therapy. Its application could be direct or through generation of tolerogenic DC as a mean of cell-based immunotherapy. Future preclinical and clinical studies should be focused towards investigating the possible application of EP in MS therapy, as well as in other autoimmune and chronic inflammatory diseases., Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) with proposed autoimmune pathogenesis. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is widely used to investigate pathogenetic mechanisms of the disease. Antigen presenting cells (APC) are major cells that are involved in the initiation of the autoimmune response against the CNS by activating CNS-specific naive CD4+ T cells. Consequently, these CD4+ T cells differentiate into effector T helper cells 1 (Th1) that produce interferon γ (IFN-γ) and Th17 cells that produce interleukin 17 (IL-17). Passing through the blood brain barrier, Th1 and Th17 cells arrive in the CNS where they become reactivated by the resident APC. Afterwards, other immune cells infiltrate the CNS, thus causing inflammation and tissue damage. The resident cells of the CNS, such as astrocytes and microglia, also contribute to the disease pathogenesis. Ethyl pyruvate (EP) is a lipophilic ester of pyruvic acid that possesses anti-oxidative and anti-inflammatory properties. The anti-encephalitogenic effect of EP in EAE and on cells of the CNS involved in the disease pathogenesis, were investigated in this study. Also, its in vitro and in vivo tolerogenic effect on dendritic cells (DC) was studied. Results showed that EP had a therapeutic effect on EAE when applied to the rats once a day, starting from the first clinical symptoms until their initial recovery. EP prevented immune cells infiltration into the CNS and inhibited T cell production of IL-17 in the spinal cord. Thus, EP restrained the inflammatory reaction in the CNS and therefore exerted its anti-encephalitogenic effect. Furthermore, treatment with EP led to the reduction of macrophages and microglia cell number, inhibition of astrocyte activity, as well as neuron destruction. Inhibition of HMGB1 (High-Mobility Group Box 1) molecule in activated macrophages/microglia was one of the mechanisms of the EP effects in the CNS. Moreover, in vitro treatment of stimulated macrophages with EP showed that EP had also an impact on APC. Treatment with EP led to reduced production of pro-inflammatory cytokines by macrophages as well as to downregulation of the expression of molecules relevant for antigen presentation. Furthermore, EP had a tolerogenic effect on the major APC, i.e. DC. Mice bone marrow derived DC were investigated. In vitro treatment of DC with EP inhibited their ability to efficiently present antigens, to activate T cells in allogeneic reaction, and to produce pro-inflammatory cytokines. Molecular mechanisms involved in the tolerogenic effects of EP on mice DC included stimulation of nuclear factor erythroid 2–related factor 2 (Nrf2) signaling, increase of heme oxygenase-1 (HO1) and NADPH-quinone oxidoreductase 1 (NQO1) expression, and inhibition of nuclear factor κB (NF-κB) transcription factor activation. Also, EP-treated DC inhibited immune response in vivo induced with complete Freund’s adjuvant in mice. Finally, the tolerogenic effects of EP were demonstrated in human monocyte derived DC (MoDC) obtained from healthy individuals and MS patients. Results of this doctoral thesis show that EP ameliorates EAE and that is also an effective tolerogenic agent that shifts DC towards immune-suppressing phenotype. Thereby, EP has the potential to be applied in MS therapy. Its application could be direct or through generation of tolerogenic DC as a mean of cell-based immunotherapy. Future preclinical and clinical studies should be focused towards investigating the possible application of EP in MS therapy, as well as in other autoimmune and chronic inflammatory diseases.",
publisher = "Belgrade: University of Belgrade, Faculty of Biology",
journal = "University of Belgrade, Faculty of Biology",
title = "Mehanizmi antiencefalitogenog dejstva etil-piruvata u eksperimentalnom autoimunskom encefalomijelitisu, Anti-encephalitogenic mechanisms of ethyl pyruvate in experimental autoimmune encephalomyelitis",
pages = "1-122",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_3425"
}

Nikolovski, N.. (2019). Mehanizmi antiencefalitogenog dejstva etil-piruvata u eksperimentalnom autoimunskom encefalomijelitisu. in University of Belgrade, Faculty of Biology
Belgrade: University of Belgrade, Faculty of Biology., 1-122.
https://hdl.handle.net/21.15107/rcub_ibiss_3425

Nikolovski N. Mehanizmi antiencefalitogenog dejstva etil-piruvata u eksperimentalnom autoimunskom encefalomijelitisu. in University of Belgrade, Faculty of Biology. 2019;:1-122.
https://hdl.handle.net/21.15107/rcub_ibiss_3425 .

Nikolovski, Neda, "Mehanizmi antiencefalitogenog dejstva etil-piruvata u eksperimentalnom autoimunskom encefalomijelitisu" in University of Belgrade, Faculty of Biology (2019):1-122,
https://hdl.handle.net/21.15107/rcub_ibiss_3425 .

TY  - CONF
AU  - Nikolovski, Neda
AU  - Miljković, Đorđe
AU  - Lavrnja, Irena
PY  - 2019
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5987
AB  - Aims: Tolerogenic dendritic cells (tolDC) have immuno-regulatory properties and they are a promising prospective therapy for multiple sclerosis, as well as for other autoimmune diseases. Ethyl pyruvate (EP) is a redox analogue of dimethyl fumarate (Tecfidera), a drug for multiple sclerosis treatment. We have recently shown that EP has the ability to direct DC towards tolDC in both murine and human DC. Therefore, we expanded our investigation to determine which mechanisms are responsible for EPimposed tolerance in DC. Therefore, we examined Nrf2 signalling pathway, HO-1 and NQO1 enzymes, and NF-κB transcription factor. Methods: C57BL/6 mice bone marrow derived DC were cultivated for 8 days in the presence of 20 ng/mL of GM-CSF without (immature DC - iDC) or with EP added on days 3 and 6 (EP-DC). In order to induce maturation, iDC and EP-DC were incubated for 15min - 4 h with 100 ng/mL lipopolysaccharide (mature - mDC and tEP-DC, respectively). After that, immunocitochemistry staining was performed. Results: Maturation of DC led to reduction of the Nrf2 and HO-1 expression, yet this reduction was prevented by EP. Also, the NQO1 expression was higher in EP-DC in comparison to iDC. However, the expression in tEP-DC was lower than in mDC, but still higher than in iDC. Finaly, unlike mDC had higher levels of nuclear NF-κB than iDC, tEP-DC had lower expression compared to EP-DC. Conclusions: EP exercises its tolerogenic potential on DC through the up-regulation of anti-oxidative signaling pathways, as well as through the inhibition of proinflammatory transcription factor NF-κB.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
T1  - Molecular Mechanisms of Ethyl Pyruvate Tolerogenic Effects on Dendritic Cells
SP  - 488
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5987
ER  - 

@conference{
author = "Nikolovski, Neda and Miljković, Đorđe and Lavrnja, Irena",
year = "2019",
abstract = "Aims: Tolerogenic dendritic cells (tolDC) have immuno-regulatory properties and they are a promising prospective therapy for multiple sclerosis, as well as for other autoimmune diseases. Ethyl pyruvate (EP) is a redox analogue of dimethyl fumarate (Tecfidera), a drug for multiple sclerosis treatment. We have recently shown that EP has the ability to direct DC towards tolDC in both murine and human DC. Therefore, we expanded our investigation to determine which mechanisms are responsible for EPimposed tolerance in DC. Therefore, we examined Nrf2 signalling pathway, HO-1 and NQO1 enzymes, and NF-κB transcription factor. Methods: C57BL/6 mice bone marrow derived DC were cultivated for 8 days in the presence of 20 ng/mL of GM-CSF without (immature DC - iDC) or with EP added on days 3 and 6 (EP-DC). In order to induce maturation, iDC and EP-DC were incubated for 15min - 4 h with 100 ng/mL lipopolysaccharide (mature - mDC and tEP-DC, respectively). After that, immunocitochemistry staining was performed. Results: Maturation of DC led to reduction of the Nrf2 and HO-1 expression, yet this reduction was prevented by EP. Also, the NQO1 expression was higher in EP-DC in comparison to iDC. However, the expression in tEP-DC was lower than in mDC, but still higher than in iDC. Finaly, unlike mDC had higher levels of nuclear NF-κB than iDC, tEP-DC had lower expression compared to EP-DC. Conclusions: EP exercises its tolerogenic potential on DC through the up-regulation of anti-oxidative signaling pathways, as well as through the inhibition of proinflammatory transcription factor NF-κB.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia",
title = "Molecular Mechanisms of Ethyl Pyruvate Tolerogenic Effects on Dendritic Cells",
pages = "488",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5987"
}

Nikolovski, N., Miljković, Đ.,& Lavrnja, I.. (2019). Molecular Mechanisms of Ethyl Pyruvate Tolerogenic Effects on Dendritic Cells. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 488.
https://hdl.handle.net/21.15107/rcub_ibiss_5987

Nikolovski N, Miljković Đ, Lavrnja I. Molecular Mechanisms of Ethyl Pyruvate Tolerogenic Effects on Dendritic Cells. in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia. 2019;:488.
https://hdl.handle.net/21.15107/rcub_ibiss_5987 .

Nikolovski, Neda, Miljković, Đorđe, Lavrnja, Irena, "Molecular Mechanisms of Ethyl Pyruvate Tolerogenic Effects on Dendritic Cells" in Book of Abstract: Federation of European Neuroscience Societies (FENS) Regional Meeting; 2019 Jul 10-13; Belgrade, Serbia (2019):488,
https://hdl.handle.net/21.15107/rcub_ibiss_5987 .

TY  - JOUR
AU  - Nikolovski, Neda
AU  - Paunović, Verica
AU  - Stojanović, Ivana D.
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S002217591930047X?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3347
AB  - Polyclonal T regulatory cells (Treg - CD4+CD25+CD127lowFoxp3+) are used in several protocols for the treatment of type 1 diabetes (T1D), multiple sclerosis and graft-versus host disease in clinical trials. However, general opinion is that autoantigen-specific Treg could be more efficient in autoimmunity suppression due to their direct effect on pathogenic autoantigen-specific effector T cells. This study describes isolation and expansion of insulin-specific Treg in vitro. Insulin-specific Treg are uniformly distributed in lymphoid tissues however their number is extremely low. To enrich the proportion of insulin-specific Treg, pure CD4+ cells were co-cultured with insulin B chain peptide-loaded dendritic cells, isolated from mice that develop T1D spontaneously - NOD mice. Insulin-specific CD4+ cell expansion peaked after 48 h of incubation and was in favour of Treg. These cells were then sorted using insulin peptide-loaded MHC class II tetramers and cultured in vitro for 48 h in the presence of TCR stimulators, TGF-β and IL-2. The proportion of gained insulin-specific cells with T regulatory phenotype (CD4+CD25highCD127lowGITR+FoxP3+) was in average between 93% and 97%. These cells have shown potent in vitro suppressive effect on T effector cells, produced IL-10 and TGF-β and expressed PD-1 and CD39. Further proliferation of these insulin-specific Treg required the presence of dendritic cells, anti-CD3 antibody and IL-2. This study provides new, reproducible experimental design for the enrichment and expansion of insulin-specific Treg that can be used for the cell-based therapy of autoimmunity.
T2  - Journal of Immunological Methods
T1  - Isolation and enrichment of mouse insulin-specific CD4+ T regulatory cells.
VL  - 470
DO  - 10.1016/j.jim.2019.04.011
SP  - 46
EP  - 54
ER  - 

@article{
author = "Nikolovski, Neda and Paunović, Verica and Stojanović, Ivana D.",
year = "2019",
abstract = "Polyclonal T regulatory cells (Treg - CD4+CD25+CD127lowFoxp3+) are used in several protocols for the treatment of type 1 diabetes (T1D), multiple sclerosis and graft-versus host disease in clinical trials. However, general opinion is that autoantigen-specific Treg could be more efficient in autoimmunity suppression due to their direct effect on pathogenic autoantigen-specific effector T cells. This study describes isolation and expansion of insulin-specific Treg in vitro. Insulin-specific Treg are uniformly distributed in lymphoid tissues however their number is extremely low. To enrich the proportion of insulin-specific Treg, pure CD4+ cells were co-cultured with insulin B chain peptide-loaded dendritic cells, isolated from mice that develop T1D spontaneously - NOD mice. Insulin-specific CD4+ cell expansion peaked after 48 h of incubation and was in favour of Treg. These cells were then sorted using insulin peptide-loaded MHC class II tetramers and cultured in vitro for 48 h in the presence of TCR stimulators, TGF-β and IL-2. The proportion of gained insulin-specific cells with T regulatory phenotype (CD4+CD25highCD127lowGITR+FoxP3+) was in average between 93% and 97%. These cells have shown potent in vitro suppressive effect on T effector cells, produced IL-10 and TGF-β and expressed PD-1 and CD39. Further proliferation of these insulin-specific Treg required the presence of dendritic cells, anti-CD3 antibody and IL-2. This study provides new, reproducible experimental design for the enrichment and expansion of insulin-specific Treg that can be used for the cell-based therapy of autoimmunity.",
journal = "Journal of Immunological Methods",
title = "Isolation and enrichment of mouse insulin-specific CD4+ T regulatory cells.",
volume = "470",
doi = "10.1016/j.jim.2019.04.011",
pages = "46-54"
}

Nikolovski, N., Paunović, V.,& Stojanović, I. D.. (2019). Isolation and enrichment of mouse insulin-specific CD4+ T regulatory cells.. in Journal of Immunological Methods, 470, 46-54.
https://doi.org/10.1016/j.jim.2019.04.011

Nikolovski N, Paunović V, Stojanović ID. Isolation and enrichment of mouse insulin-specific CD4+ T regulatory cells.. in Journal of Immunological Methods. 2019;470:46-54.
doi:10.1016/j.jim.2019.04.011 .

Nikolovski, Neda, Paunović, Verica, Stojanović, Ivana D., "Isolation and enrichment of mouse insulin-specific CD4+ T regulatory cells." in Journal of Immunological Methods, 470 (2019):46-54,
https://doi.org/10.1016/j.jim.2019.04.011 . .

TY  - JOUR
AU  - Nikolovski, Neda
AU  - Mansilla, María José
AU  - Jevtić, Bojan
AU  - Navarro-Barriuso, Juan
AU  - Saksida, Tamara
AU  - Martínez-Cáceres, Eva M.
AU  - Miljković, Đorđe
PY  - 2019
UR  - https://www.frontiersin.org/article/10.3389/fimmu.2019.00157/full
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC6374627
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3280
AB  - Dendritic cells (DC) are professional antigen presenting cells that have a key role in shaping the immune response. Tolerogenic DC (tolDC) have immuno-regulatory properties and they are a promising prospective therapy for multiple sclerosis and other autoimmune diseases. Ethyl pyruvate (EP) is a redox analog of dimethyl fumarate (Tecfidera), a drug for multiple sclerosis treatment. We have recently shown that EP ameliorates experimental autoimmune encephalomyelitis, a multiple sclerosis murine model. Here, we expanded our study to its tolerogenic effects on DC. Phenotypic analysis has shown that DC obtained from mice or humans reduce expression of molecules required for T cell activation such as CD86, CD83, and HLA-DR under the influence of EP, while CD11c expression and viability of DC are not affected. Furthermore, EP-treated DC restrain proliferation and modulate cytokine production of allogeneic lymphocytes. These results demonstrate that EP has the ability to direct DC toward tolDC.
T2  - Frontiers in Immunology
T1  - Ethyl Pyruvate Induces Tolerogenic Dendritic Cells.
VL  - 10
DO  - 10.3389/fimmu.2019.00157
SP  - 157
ER  - 

@article{
author = "Nikolovski, Neda and Mansilla, María José and Jevtić, Bojan and Navarro-Barriuso, Juan and Saksida, Tamara and Martínez-Cáceres, Eva M. and Miljković, Đorđe",
year = "2019",
abstract = "Dendritic cells (DC) are professional antigen presenting cells that have a key role in shaping the immune response. Tolerogenic DC (tolDC) have immuno-regulatory properties and they are a promising prospective therapy for multiple sclerosis and other autoimmune diseases. Ethyl pyruvate (EP) is a redox analog of dimethyl fumarate (Tecfidera), a drug for multiple sclerosis treatment. We have recently shown that EP ameliorates experimental autoimmune encephalomyelitis, a multiple sclerosis murine model. Here, we expanded our study to its tolerogenic effects on DC. Phenotypic analysis has shown that DC obtained from mice or humans reduce expression of molecules required for T cell activation such as CD86, CD83, and HLA-DR under the influence of EP, while CD11c expression and viability of DC are not affected. Furthermore, EP-treated DC restrain proliferation and modulate cytokine production of allogeneic lymphocytes. These results demonstrate that EP has the ability to direct DC toward tolDC.",
journal = "Frontiers in Immunology",
title = "Ethyl Pyruvate Induces Tolerogenic Dendritic Cells.",
volume = "10",
doi = "10.3389/fimmu.2019.00157",
pages = "157"
}

Nikolovski, N., Mansilla, M. J., Jevtić, B., Navarro-Barriuso, J., Saksida, T., Martínez-Cáceres, E. M.,& Miljković, Đ.. (2019). Ethyl Pyruvate Induces Tolerogenic Dendritic Cells.. in Frontiers in Immunology, 10, 157.
https://doi.org/10.3389/fimmu.2019.00157

Nikolovski N, Mansilla MJ, Jevtić B, Navarro-Barriuso J, Saksida T, Martínez-Cáceres EM, Miljković Đ. Ethyl Pyruvate Induces Tolerogenic Dendritic Cells.. in Frontiers in Immunology. 2019;10:157.
doi:10.3389/fimmu.2019.00157 .

Nikolovski, Neda, Mansilla, María José, Jevtić, Bojan, Navarro-Barriuso, Juan, Saksida, Tamara, Martínez-Cáceres, Eva M., Miljković, Đorđe, "Ethyl Pyruvate Induces Tolerogenic Dendritic Cells." in Frontiers in Immunology, 10 (2019):157,
https://doi.org/10.3389/fimmu.2019.00157 . .

TY  - JOUR
AU  - Stanisavljević, Suzana
AU  - Čepić, Aleksa
AU  - Bojić, Svetlana
AU  - Veljović, Katarina
AU  - Mihajlović, Sanja
AU  - Nikolovski, Neda
AU  - Jevtić, Bojan
AU  - Momčilović, Miljana
AU  - Lazarević, Milica
AU  - Mostarica Stojković, Marija
AU  - Miljković, Đorđe
AU  - Golić, Nataša
PY  - 2019
UR  - http://www.nature.com/articles/s41598-018-37505-7
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC6351648
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3264
AB  - Gut microbiota dysbiosis has been considered the essential element in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Antibiotics were administered orally to Dark Agouti (DA) rats early in their life with the aim of perturbing gut microbiota and investigating the effects of such intervention on the course of EAE. As a result, the diversity of the gut microbiota was reduced under the influence of antibiotics. Mainly, Firmicutes and Actinobacteria were replaced by Proteobacteria and Bacteroidetes, while decreased proportions of Clostridia and Bacilli classes were accompanied by an increase in Gamma-Proteobacteria in antibiotic-treated animals. Interestingly, a notable decrease in the Helicobacteraceae, Spirochaetaceae and Turicibacteriaceae was scored in antibiotic-treated groups. Also, levels of short chain fatty acids were reduced in the faeces of antibiotic-treated rats. Consequently, aggravation of EAE, paralleled with stronger immune response in lymph nodes draining the site of immunization, and increased inflammation within the CNS, were observed in antibiotic-treated DA rats. Thus, the alteration of gut microbiota leads to an escalation of CNS-directed autoimmunity in DA rats. The results of this study indicate that antibiotic use in early life may have subsequent unfavourable effects on the regulation of the immune system.
T2  - Scientific Reports
T1  - Oral neonatal antibiotic treatment perturbs gut microbiota and aggravates central nervous system autoimmunity in Dark Agouti rats.
IS  - 1
VL  - 9
DO  - 10.1038/s41598-018-37505-7
SP  - 918
ER  - 

@article{
author = "Stanisavljević, Suzana and Čepić, Aleksa and Bojić, Svetlana and Veljović, Katarina and Mihajlović, Sanja and Nikolovski, Neda and Jevtić, Bojan and Momčilović, Miljana and Lazarević, Milica and Mostarica Stojković, Marija and Miljković, Đorđe and Golić, Nataša",
year = "2019",
abstract = "Gut microbiota dysbiosis has been considered the essential element in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Antibiotics were administered orally to Dark Agouti (DA) rats early in their life with the aim of perturbing gut microbiota and investigating the effects of such intervention on the course of EAE. As a result, the diversity of the gut microbiota was reduced under the influence of antibiotics. Mainly, Firmicutes and Actinobacteria were replaced by Proteobacteria and Bacteroidetes, while decreased proportions of Clostridia and Bacilli classes were accompanied by an increase in Gamma-Proteobacteria in antibiotic-treated animals. Interestingly, a notable decrease in the Helicobacteraceae, Spirochaetaceae and Turicibacteriaceae was scored in antibiotic-treated groups. Also, levels of short chain fatty acids were reduced in the faeces of antibiotic-treated rats. Consequently, aggravation of EAE, paralleled with stronger immune response in lymph nodes draining the site of immunization, and increased inflammation within the CNS, were observed in antibiotic-treated DA rats. Thus, the alteration of gut microbiota leads to an escalation of CNS-directed autoimmunity in DA rats. The results of this study indicate that antibiotic use in early life may have subsequent unfavourable effects on the regulation of the immune system.",
journal = "Scientific Reports",
title = "Oral neonatal antibiotic treatment perturbs gut microbiota and aggravates central nervous system autoimmunity in Dark Agouti rats.",
number = "1",
volume = "9",
doi = "10.1038/s41598-018-37505-7",
pages = "918"
}

Stanisavljević, S., Čepić, A., Bojić, S., Veljović, K., Mihajlović, S., Nikolovski, N., Jevtić, B., Momčilović, M., Lazarević, M., Mostarica Stojković, M., Miljković, Đ.,& Golić, N.. (2019). Oral neonatal antibiotic treatment perturbs gut microbiota and aggravates central nervous system autoimmunity in Dark Agouti rats.. in Scientific Reports, 9(1), 918.
https://doi.org/10.1038/s41598-018-37505-7

Stanisavljević S, Čepić A, Bojić S, Veljović K, Mihajlović S, Nikolovski N, Jevtić B, Momčilović M, Lazarević M, Mostarica Stojković M, Miljković Đ, Golić N. Oral neonatal antibiotic treatment perturbs gut microbiota and aggravates central nervous system autoimmunity in Dark Agouti rats.. in Scientific Reports. 2019;9(1):918.
doi:10.1038/s41598-018-37505-7 .

Stanisavljević, Suzana, Čepić, Aleksa, Bojić, Svetlana, Veljović, Katarina, Mihajlović, Sanja, Nikolovski, Neda, Jevtić, Bojan, Momčilović, Miljana, Lazarević, Milica, Mostarica Stojković, Marija, Miljković, Đorđe, Golić, Nataša, "Oral neonatal antibiotic treatment perturbs gut microbiota and aggravates central nervous system autoimmunity in Dark Agouti rats." in Scientific Reports, 9, no. 1 (2019):918,
https://doi.org/10.1038/s41598-018-37505-7 . .

TY  - JOUR
AU  - Živanović, Jasmina
AU  - Jarić, Ivana
AU  - Ajdžanović, Vladimir
AU  - Mojić, Marija
AU  - Miler, Marko
AU  - Šošić-Jurjević, Branka 
AU  - Milošević, Verica
AU  - Filipović, Branko
PY  - 2019
UR  - https://www.sciencedirect.com/science/article/pii/S0940960218301080?via%3Dihub
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3150
AB  - In a rat model of the andropause we aimed to examine the influence of daidzein, soy isoflavone, on the structure and function of parathyroid glands (PTG) and the expression levels of some of the crucial regulators of Ca2+ and Pi homeostasis in the kidney, and to compare these effects with the effects of estradiol, serving as a positive control. Middle-aged (16-month-old) male Wistar rats were divided into the following groups: sham-operated (SO), orchidectomized (Orx), orchidectomized and estradiol-treated (Orx+E; 0.625mg/kg b.w./day, s.c.) as well as orchidectomized and daidzein-treated (Orx+D; 30mg/kg b.w./day, s.c.) group. Every treated group had a corresponding control group. PTH serum concentration was decreased in Orx+E and Orx+D groups by 10% and 21% (p<0.05) respectively, in comparison with the Orx. PTG volume was decreased in Orx+E group by 16% (p<0.05), when compared to the Orx. In Orx+E group expression of NaPi 2a was lower (p<0.05), while NaPi 2a abundance in Orx+D animals was increased (p<0.05), when compared to Orx. Expression of PTH1R was increased (p<0.05) in Orx+E group, while in Orx+D animals the same parameter was decreased (p<0.05), in comparison with Orx. Klotho expression was elevated (p<0.05) in Orx+D rats, in regard to Orx. Orx+D induced reduction in Ca2+/creatinine and Pi/creatinine ratio in urine by 32% and 16% (p<0.05) respectively, in comparison with Orx. In conclusion, presented results indicate the more coherent beneficial effects of daidzein compared to estradiol, on disturbed Ca2+ and Pi homeostasis, and presumably on bone health, in the aging male rats.
T2  - Annals of Anatomy = Anatomischer Anzeiger
T1  - Daidzein upregulates anti-aging protein Klotho and NaPi 2a cotransporter in a rat model of the andropause.
VL  - 221
DO  - 10.1016/j.aanat.2018.08.001
SP  - 27
EP  - 37
ER  - 

@article{
author = "Živanović, Jasmina and Jarić, Ivana and Ajdžanović, Vladimir and Mojić, Marija and Miler, Marko and Šošić-Jurjević, Branka  and Milošević, Verica and Filipović, Branko",
year = "2019",
abstract = "In a rat model of the andropause we aimed to examine the influence of daidzein, soy isoflavone, on the structure and function of parathyroid glands (PTG) and the expression levels of some of the crucial regulators of Ca2+ and Pi homeostasis in the kidney, and to compare these effects with the effects of estradiol, serving as a positive control. Middle-aged (16-month-old) male Wistar rats were divided into the following groups: sham-operated (SO), orchidectomized (Orx), orchidectomized and estradiol-treated (Orx+E; 0.625mg/kg b.w./day, s.c.) as well as orchidectomized and daidzein-treated (Orx+D; 30mg/kg b.w./day, s.c.) group. Every treated group had a corresponding control group. PTH serum concentration was decreased in Orx+E and Orx+D groups by 10% and 21% (p<0.05) respectively, in comparison with the Orx. PTG volume was decreased in Orx+E group by 16% (p<0.05), when compared to the Orx. In Orx+E group expression of NaPi 2a was lower (p<0.05), while NaPi 2a abundance in Orx+D animals was increased (p<0.05), when compared to Orx. Expression of PTH1R was increased (p<0.05) in Orx+E group, while in Orx+D animals the same parameter was decreased (p<0.05), in comparison with Orx. Klotho expression was elevated (p<0.05) in Orx+D rats, in regard to Orx. Orx+D induced reduction in Ca2+/creatinine and Pi/creatinine ratio in urine by 32% and 16% (p<0.05) respectively, in comparison with Orx. In conclusion, presented results indicate the more coherent beneficial effects of daidzein compared to estradiol, on disturbed Ca2+ and Pi homeostasis, and presumably on bone health, in the aging male rats.",
journal = "Annals of Anatomy = Anatomischer Anzeiger",
title = "Daidzein upregulates anti-aging protein Klotho and NaPi 2a cotransporter in a rat model of the andropause.",
volume = "221",
doi = "10.1016/j.aanat.2018.08.001",
pages = "27-37"
}

Živanović, J., Jarić, I., Ajdžanović, V., Mojić, M., Miler, M., Šošić-Jurjević, B., Milošević, V.,& Filipović, B.. (2019). Daidzein upregulates anti-aging protein Klotho and NaPi 2a cotransporter in a rat model of the andropause.. in Annals of Anatomy = Anatomischer Anzeiger, 221, 27-37.
https://doi.org/10.1016/j.aanat.2018.08.001

Živanović J, Jarić I, Ajdžanović V, Mojić M, Miler M, Šošić-Jurjević B, Milošević V, Filipović B. Daidzein upregulates anti-aging protein Klotho and NaPi 2a cotransporter in a rat model of the andropause.. in Annals of Anatomy = Anatomischer Anzeiger. 2019;221:27-37.
doi:10.1016/j.aanat.2018.08.001 .

Živanović, Jasmina, Jarić, Ivana, Ajdžanović, Vladimir, Mojić, Marija, Miler, Marko, Šošić-Jurjević, Branka , Milošević, Verica, Filipović, Branko, "Daidzein upregulates anti-aging protein Klotho and NaPi 2a cotransporter in a rat model of the andropause." in Annals of Anatomy = Anatomischer Anzeiger, 221 (2019):27-37,
https://doi.org/10.1016/j.aanat.2018.08.001 . .

TY  - JOUR
AU  - Schwarze, Benedikt
AU  - Jelača, Sanja
AU  - Welcke, Linda
AU  - Maksimović-Ivanić, Danijela
AU  - Mijatović, Sanja
AU  - Hey-Hawkins, Evamarie
PY  - 2019
UR  - https://onlinelibrary.wiley.com/doi/abs/10.1002/cmdc.201900554
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3531
AB  - Investigations on the antitumor activity of metallacarboranes are sparse in the literature and limited to a handful of ruthena- and molybdacarboranes. In this study, the molybdacarborane fragment [3-(CO)2 -closo-3,1,2-MoC2 B9 H11 ] was combined with a vector molecule, inspired by the well-known drug tamoxifen or 4,4'-dihydroxytamoxifen (TAM-diOH). The molybdacarborane derivative [3,3-{4-[1,1-bis(4-hydroxyphenyl)but-1-en-2-yl]-2,2'-bipyridine-κ2 N,N'}-3-(CO)2 -closo-3,1,2-MoC2 B9 H11 ] (10), as well as the ligand itself 4-[1,1-bis(4-hydroxyphenyl)but-1-en-2-yl]-2,2'-bipyridine (6) showed cytotoxic activities in the low micromolar range against breast adenocarcinoma (MDA-MB-231, MDA-MB-361 and MCF-7), human glioblastoma (LN-229) and human glioma (U-251) cell lines. In addition, compounds 6 and 10 were found to induce senescence and cytodestructive autophagy, lower ROS/RNS levels, but only the molybdacarborane 10 induced a strong increase of nitric oxide (NO) concentration in the MCF-7 cells.
T2  - ChemMedChem
T1  - 2,2'-Bipyridine-Modified Tamoxifen: A Versatile Vector for Molybdacarboranes.
IS  - 24
VL  - 14
DO  - 10.1002/cmdc.201900554
SP  - 2075
EP  - 2083
ER  - 

@article{
author = "Schwarze, Benedikt and Jelača, Sanja and Welcke, Linda and Maksimović-Ivanić, Danijela and Mijatović, Sanja and Hey-Hawkins, Evamarie",
year = "2019",
abstract = "Investigations on the antitumor activity of metallacarboranes are sparse in the literature and limited to a handful of ruthena- and molybdacarboranes. In this study, the molybdacarborane fragment [3-(CO)2 -closo-3,1,2-MoC2 B9 H11 ] was combined with a vector molecule, inspired by the well-known drug tamoxifen or 4,4'-dihydroxytamoxifen (TAM-diOH). The molybdacarborane derivative [3,3-{4-[1,1-bis(4-hydroxyphenyl)but-1-en-2-yl]-2,2'-bipyridine-κ2 N,N'}-3-(CO)2 -closo-3,1,2-MoC2 B9 H11 ] (10), as well as the ligand itself 4-[1,1-bis(4-hydroxyphenyl)but-1-en-2-yl]-2,2'-bipyridine (6) showed cytotoxic activities in the low micromolar range against breast adenocarcinoma (MDA-MB-231, MDA-MB-361 and MCF-7), human glioblastoma (LN-229) and human glioma (U-251) cell lines. In addition, compounds 6 and 10 were found to induce senescence and cytodestructive autophagy, lower ROS/RNS levels, but only the molybdacarborane 10 induced a strong increase of nitric oxide (NO) concentration in the MCF-7 cells.",
journal = "ChemMedChem",
title = "2,2'-Bipyridine-Modified Tamoxifen: A Versatile Vector for Molybdacarboranes.",
number = "24",
volume = "14",
doi = "10.1002/cmdc.201900554",
pages = "2075-2083"
}

Schwarze, B., Jelača, S., Welcke, L., Maksimović-Ivanić, D., Mijatović, S.,& Hey-Hawkins, E.. (2019). 2,2'-Bipyridine-Modified Tamoxifen: A Versatile Vector for Molybdacarboranes.. in ChemMedChem, 14(24), 2075-2083.
https://doi.org/10.1002/cmdc.201900554

Schwarze B, Jelača S, Welcke L, Maksimović-Ivanić D, Mijatović S, Hey-Hawkins E. 2,2'-Bipyridine-Modified Tamoxifen: A Versatile Vector for Molybdacarboranes.. in ChemMedChem. 2019;14(24):2075-2083.
doi:10.1002/cmdc.201900554 .

Schwarze, Benedikt, Jelača, Sanja, Welcke, Linda, Maksimović-Ivanić, Danijela, Mijatović, Sanja, Hey-Hawkins, Evamarie, "2,2'-Bipyridine-Modified Tamoxifen: A Versatile Vector for Molybdacarboranes." in ChemMedChem, 14, no. 24 (2019):2075-2083,
https://doi.org/10.1002/cmdc.201900554 . .

TY  - JOUR
AU  - Paskaš, Svetlana
AU  - Krajnović, Tamara
AU  - Basile, Maria S.
AU  - Dunđerović, Duško
AU  - Cavalli, Eugenio
AU  - Mangano, Katia
AU  - Mammana, Santa
AU  - Al-Abed, Yousef
AU  - Nicoletti, Ferdinando
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
PY  - 2019
UR  - https://onlinelibrary.wiley.com/doi/abs/10.1002/mc.23020
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3339
AB  - The main focus of this study is exploring the effect and mechanism of two HIV-protease inhibitors: Ritonavir and Ritonavir-nitric oxide (Ritonavir-NO) on in vitro growth of melanoma cell lines. NO modification significantly improved the antitumor potential of Ritonavir, as the IC50 values of Ritonavir-NO were approximately two times lower than IC50 values of the parental compound. Our results showed for the first time, that both compounds induced senescence in primary and metastatic melanoma cell lines. This transformation was manifested as a change in cell morphology, enlargement of nuclei, increased cellular granulation, upregulation of β-galactosidase activity, lipofuscin granules appearance, higher production of reactive oxygen species and persistent inhibition of proliferation. The expression of p53, as one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir-NO treatment only in metastatic B16F10 cells, ranking it as a late-response event. The development of senescent phenotype was consistent with the alteration of the cytoskeleton-as we observed diminished expression of vinculin, α-actin, and β-tubulin. Permanent inhibition of S6 protein by Ritonavir-NO, but not Ritonavir, could be responsible for a stronger antiproliferative potential of the NO-modified compound. Taken together, induction of senescent phenotype may provide an excellent platform for developing therapeutic approaches based on selective killing of senescent cells.
T2  - Molecular Carcinogenesis
T2  - Molecular Carcinogenesis
T1  - Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma.
DO  - 10.1002/mc.23020
ER  - 

@article{
author = "Paskaš, Svetlana and Krajnović, Tamara and Basile, Maria S. and Dunđerović, Duško and Cavalli, Eugenio and Mangano, Katia and Mammana, Santa and Al-Abed, Yousef and Nicoletti, Ferdinando and Mijatović, Sanja and Maksimović-Ivanić, Danijela",
year = "2019",
abstract = "The main focus of this study is exploring the effect and mechanism of two HIV-protease inhibitors: Ritonavir and Ritonavir-nitric oxide (Ritonavir-NO) on in vitro growth of melanoma cell lines. NO modification significantly improved the antitumor potential of Ritonavir, as the IC50 values of Ritonavir-NO were approximately two times lower than IC50 values of the parental compound. Our results showed for the first time, that both compounds induced senescence in primary and metastatic melanoma cell lines. This transformation was manifested as a change in cell morphology, enlargement of nuclei, increased cellular granulation, upregulation of β-galactosidase activity, lipofuscin granules appearance, higher production of reactive oxygen species and persistent inhibition of proliferation. The expression of p53, as one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir-NO treatment only in metastatic B16F10 cells, ranking it as a late-response event. The development of senescent phenotype was consistent with the alteration of the cytoskeleton-as we observed diminished expression of vinculin, α-actin, and β-tubulin. Permanent inhibition of S6 protein by Ritonavir-NO, but not Ritonavir, could be responsible for a stronger antiproliferative potential of the NO-modified compound. Taken together, induction of senescent phenotype may provide an excellent platform for developing therapeutic approaches based on selective killing of senescent cells.",
journal = "Molecular Carcinogenesis, Molecular Carcinogenesis",
title = "Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma.",
doi = "10.1002/mc.23020"
}

Paskaš, S., Krajnović, T., Basile, M. S., Dunđerović, D., Cavalli, E., Mangano, K., Mammana, S., Al-Abed, Y., Nicoletti, F., Mijatović, S.,& Maksimović-Ivanić, D.. (2019). Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma.. in Molecular Carcinogenesis.
https://doi.org/10.1002/mc.23020

Paskaš S, Krajnović T, Basile MS, Dunđerović D, Cavalli E, Mangano K, Mammana S, Al-Abed Y, Nicoletti F, Mijatović S, Maksimović-Ivanić D. Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma.. in Molecular Carcinogenesis. 2019;.
doi:10.1002/mc.23020 .

Paskaš, Svetlana, Krajnović, Tamara, Basile, Maria S., Dunđerović, Duško, Cavalli, Eugenio, Mangano, Katia, Mammana, Santa, Al-Abed, Yousef, Nicoletti, Ferdinando, Mijatović, Sanja, Maksimović-Ivanić, Danijela, "Senescence as a main mechanism of Ritonavir and Ritonavir-NO action against melanoma." in Molecular Carcinogenesis (2019),
https://doi.org/10.1002/mc.23020 . .

TY  - CONF
AU  - Marković, Milan
AU  - Marković, Katarina
AU  - Mirkov, Ivana
AU  - Tucović, Dina
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
AU  - Popov Aleksandrov, Aleksandra
PY  - 2019
UR  - https://www.isos.rs/congress2019-abstract-book
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3580
UR  - https://radar.ibiss.bg.ac.rs/handle/handle/123456789/3558
AB  - Cadmium (Cd) is one of the most cytotoxic agents and environmental contaminants, which can cause serial health problems in various organs such as liver, kidney, testis, bone, nervous tissue and immune system. Furthermore, Cd is classified as a human and animal carcinogen agent. Despite the fact that Cd accumulates in the skin, there is a lack of evidence about its involvement in skin cancer biology. Skin cancer is one of the most common cancers worldwide, with melanoma as the most lethal type. Based on that, we set up the study to examine the effect of cadmium on the B16 melanoma cell line, measuring viability by MTT and crystal violet (CV) tests, proliferation rate (CFSE), ROS production (DHR), migration (scratch test) and adhesion on matrigel. The results showed that non-cytotoxic doses of cadmium (ranging from 0,3-2,5µM) increased viability, proliferation, and migration of B16 cells, while at the same time slightly promoted ROS production. Otherwise, pronounced oxidative stress induced by higher doses (ranging from 5-20µM) led to cell death. Summary, these results showed that low doses of cadmium could upregulate B16 melanoma cell line growth and migration probably through moderate ROS/RNS generation and thus their ability to modulate relevant signaling pathways involved in cancer progression. Considering that, underlying mechanisms of Cd impact on melanoma cell lines proliferation, migration and invasiveness needs to be clarified in vitro, as well as its relevance for in vivo system.
PB  - Belgrade: University of Belgrade Institute for Biological Research "Siniša Stanković" National Institute of Republic of Serbia
PB  - Belgrade: Immunological Society of Serbia
C3  - Saksida T, Stanisavljević S, Miljković Đ, editors. Immunology at the Confluence of Multidisciplinary Approaches : abstract book; 2019 Dec 6-8; Belgrade, Serbia
T1  - Effect of non-cytotoxic doses of cadmium on the B16 melanoma cell line
SP  - 123
EP  - 123
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_3580
ER  - 

@conference{
author = "Marković, Milan and Marković, Katarina and Mirkov, Ivana and Tucović, Dina and Mijatović, Sanja and Maksimović-Ivanić, Danijela and Popov Aleksandrov, Aleksandra",
year = "2019",
abstract = "Cadmium (Cd) is one of the most cytotoxic agents and environmental contaminants, which can cause serial health problems in various organs such as liver, kidney, testis, bone, nervous tissue and immune system. Furthermore, Cd is classified as a human and animal carcinogen agent. Despite the fact that Cd accumulates in the skin, there is a lack of evidence about its involvement in skin cancer biology. Skin cancer is one of the most common cancers worldwide, with melanoma as the most lethal type. Based on that, we set up the study to examine the effect of cadmium on the B16 melanoma cell line, measuring viability by MTT and crystal violet (CV) tests, proliferation rate (CFSE), ROS production (DHR), migration (scratch test) and adhesion on matrigel. The results showed that non-cytotoxic doses of cadmium (ranging from 0,3-2,5µM) increased viability, proliferation, and migration of B16 cells, while at the same time slightly promoted ROS production. Otherwise, pronounced oxidative stress induced by higher doses (ranging from 5-20µM) led to cell death. Summary, these results showed that low doses of cadmium could upregulate B16 melanoma cell line growth and migration probably through moderate ROS/RNS generation and thus their ability to modulate relevant signaling pathways involved in cancer progression. Considering that, underlying mechanisms of Cd impact on melanoma cell lines proliferation, migration and invasiveness needs to be clarified in vitro, as well as its relevance for in vivo system.",
publisher = "Belgrade: University of Belgrade Institute for Biological Research "Siniša Stanković" National Institute of Republic of Serbia, Belgrade: Immunological Society of Serbia",
journal = "Saksida T, Stanisavljević S, Miljković Đ, editors. Immunology at the Confluence of Multidisciplinary Approaches : abstract book; 2019 Dec 6-8; Belgrade, Serbia",
title = "Effect of non-cytotoxic doses of cadmium on the B16 melanoma cell line",
pages = "123-123",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_3580"
}

Marković, M., Marković, K., Mirkov, I., Tucović, D., Mijatović, S., Maksimović-Ivanić, D.,& Popov Aleksandrov, A.. (2019). Effect of non-cytotoxic doses of cadmium on the B16 melanoma cell line. in Saksida T, Stanisavljević S, Miljković Đ, editors. Immunology at the Confluence of Multidisciplinary Approaches : abstract book; 2019 Dec 6-8; Belgrade, Serbia
Belgrade: University of Belgrade Institute for Biological Research "Siniša Stanković" National Institute of Republic of Serbia., 123-123.
https://hdl.handle.net/21.15107/rcub_ibiss_3580

Marković M, Marković K, Mirkov I, Tucović D, Mijatović S, Maksimović-Ivanić D, Popov Aleksandrov A. Effect of non-cytotoxic doses of cadmium on the B16 melanoma cell line. in Saksida T, Stanisavljević S, Miljković Đ, editors. Immunology at the Confluence of Multidisciplinary Approaches : abstract book; 2019 Dec 6-8; Belgrade, Serbia. 2019;:123-123.
https://hdl.handle.net/21.15107/rcub_ibiss_3580 .

Marković, Milan, Marković, Katarina, Mirkov, Ivana, Tucović, Dina, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Popov Aleksandrov, Aleksandra, "Effect of non-cytotoxic doses of cadmium on the B16 melanoma cell line" in Saksida T, Stanisavljević S, Miljković Đ, editors. Immunology at the Confluence of Multidisciplinary Approaches : abstract book; 2019 Dec 6-8; Belgrade, Serbia (2019):123-123,
https://hdl.handle.net/21.15107/rcub_ibiss_3580 .

TY  - JOUR
AU  - Buzharevski, Antonio
AU  - Paskaš, Svetlana
AU  - Laube, Markus
AU  - Lönnecke, Peter
AU  - Neumann, Wilma
AU  - Murganić, Blagoje
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
AU  - Pietzsch, Jens
AU  - Hey-Hawkins, Evamarie
PY  - 2019
UR  - http://pubs.acs.org/doi/10.1021/acsomega.9b00412
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3366
AB  - Ketoprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID) that also exhibits cytotoxic activity against various cancers. This makes ketoprofen an attractive structural lead for the development of new NSAIDs and cytotoxic agents. Recently, the incorporation of carboranes as phenyl mimetics in structures of established drugs has emerged as an attractive strategy in drug design. Herein, we report the synthesis and evaluation of four novel carborane-containing derivatives of ketoprofen, two of which are prodrug esters with an nitric oxide-releasing moiety. One of these prodrug esters exhibited high cytostatic activity against melanoma and colon cancer cell lines. The most pronounced activity was found in cell lines that are sensitive to oxidative stress, which was apparently induced by the ketoprofen analogue.
T2  - ACS Omega
T2  - ACS Omega
T1  - Carboranyl Analogues of Ketoprofen with Cytostatic Activity against Human Melanoma and Colon Cancer Cell Lines
IS  - 5
VL  - 4
DO  - 10.1021/acsomega.9b00412
SP  - 8824
EP  - 8833
ER  - 

@article{
author = "Buzharevski, Antonio and Paskaš, Svetlana and Laube, Markus and Lönnecke, Peter and Neumann, Wilma and Murganić, Blagoje and Mijatović, Sanja and Maksimović-Ivanić, Danijela and Pietzsch, Jens and Hey-Hawkins, Evamarie",
year = "2019",
abstract = "Ketoprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID) that also exhibits cytotoxic activity against various cancers. This makes ketoprofen an attractive structural lead for the development of new NSAIDs and cytotoxic agents. Recently, the incorporation of carboranes as phenyl mimetics in structures of established drugs has emerged as an attractive strategy in drug design. Herein, we report the synthesis and evaluation of four novel carborane-containing derivatives of ketoprofen, two of which are prodrug esters with an nitric oxide-releasing moiety. One of these prodrug esters exhibited high cytostatic activity against melanoma and colon cancer cell lines. The most pronounced activity was found in cell lines that are sensitive to oxidative stress, which was apparently induced by the ketoprofen analogue.",
journal = "ACS Omega, ACS Omega",
title = "Carboranyl Analogues of Ketoprofen with Cytostatic Activity against Human Melanoma and Colon Cancer Cell Lines",
number = "5",
volume = "4",
doi = "10.1021/acsomega.9b00412",
pages = "8824-8833"
}

Buzharevski, A., Paskaš, S., Laube, M., Lönnecke, P., Neumann, W., Murganić, B., Mijatović, S., Maksimović-Ivanić, D., Pietzsch, J.,& Hey-Hawkins, E.. (2019). Carboranyl Analogues of Ketoprofen with Cytostatic Activity against Human Melanoma and Colon Cancer Cell Lines. in ACS Omega, 4(5), 8824-8833.
https://doi.org/10.1021/acsomega.9b00412

Buzharevski A, Paskaš S, Laube M, Lönnecke P, Neumann W, Murganić B, Mijatović S, Maksimović-Ivanić D, Pietzsch J, Hey-Hawkins E. Carboranyl Analogues of Ketoprofen with Cytostatic Activity against Human Melanoma and Colon Cancer Cell Lines. in ACS Omega. 2019;4(5):8824-8833.
doi:10.1021/acsomega.9b00412 .

Buzharevski, Antonio, Paskaš, Svetlana, Laube, Markus, Lönnecke, Peter, Neumann, Wilma, Murganić, Blagoje, Mijatović, Sanja, Maksimović-Ivanić, Danijela, Pietzsch, Jens, Hey-Hawkins, Evamarie, "Carboranyl Analogues of Ketoprofen with Cytostatic Activity against Human Melanoma and Colon Cancer Cell Lines" in ACS Omega, 4, no. 5 (2019):8824-8833,
https://doi.org/10.1021/acsomega.9b00412 . .

TY  - JOUR
AU  - Paskaš, Svetlana
AU  - Krajnović, Tamara
AU  - Basile, Maria S.
AU  - Dunđerović, Duško
AU  - Cavalli, Eugenio
AU  - Mangano, Katia
AU  - Mammana, Sant
AU  - Al‐Abed, Yousef
AU  - Nicoletti, Ferdinando
AU  - Mijatović, Sanja
AU  - Maksimović-Ivanić, Danijela
PY  - 2019
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3780
AB  - The main focus of this study is exploring the effect and mechanism of two HIVprotease
inhibitors: Ritonavir and Ritonavir‐nitric oxide (Ritonavir‐NO) on in vitro
growth of melanoma cell lines. NO modification significantly improved the antitumor
potential of Ritonavir, as the IC50 values of Ritonavir‐NO were approximately two
times lower than IC50 values of the parental compound. Our results showed for the
first time, that both compounds induced senescence in primary and metastatic
melanoma cell lines. This transformation was manifested as a change in cell
morphology, enlargement of nuclei, increased cellular granulation, upregulation of
β‐galactosidase activity, lipofuscin granules appearance, higher production of reactive
oxygen species and persistent inhibition of proliferation. The expression of p53, as
one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir‐
NO treatment only in metastatic B16F10 cells, ranking it as a late‐response event.
The development of senescent phenotype was consistent with the alteration of
the cytoskeleton—as we observed diminished expression of vinculin, α‐actin, and
β‐tubulin. Permanent inhibition of S6 protein by Ritonavir‐NO, but not Ritonavir,
could be responsible for a stronger antiproliferative potential of the NO‐modified
compound. Taken together, induction of senescent phenotype may provide an
excellent platform for developing therapeutic approaches based on selective killing of
senescent cells.
PB  - New Jersey: Wiley-VCH Verlag GmbH & Co
T2  - Molecular Carcinogenesis
T1  - Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma
IS  - 8
VL  - 58
DO  - 10.1002/mc.23020
SP  - 1362
EP  - 1375
ER  - 

@article{
author = "Paskaš, Svetlana and Krajnović, Tamara and Basile, Maria S. and Dunđerović, Duško and Cavalli, Eugenio and Mangano, Katia and Mammana, Sant and Al‐Abed, Yousef and Nicoletti, Ferdinando and Mijatović, Sanja and Maksimović-Ivanić, Danijela",
year = "2019",
abstract = "The main focus of this study is exploring the effect and mechanism of two HIVprotease
inhibitors: Ritonavir and Ritonavir‐nitric oxide (Ritonavir‐NO) on in vitro
growth of melanoma cell lines. NO modification significantly improved the antitumor
potential of Ritonavir, as the IC50 values of Ritonavir‐NO were approximately two
times lower than IC50 values of the parental compound. Our results showed for the
first time, that both compounds induced senescence in primary and metastatic
melanoma cell lines. This transformation was manifested as a change in cell
morphology, enlargement of nuclei, increased cellular granulation, upregulation of
β‐galactosidase activity, lipofuscin granules appearance, higher production of reactive
oxygen species and persistent inhibition of proliferation. The expression of p53, as
one of the key regulators of senescence, was upregulated after 48 hours of Ritonavir‐
NO treatment only in metastatic B16F10 cells, ranking it as a late‐response event.
The development of senescent phenotype was consistent with the alteration of
the cytoskeleton—as we observed diminished expression of vinculin, α‐actin, and
β‐tubulin. Permanent inhibition of S6 protein by Ritonavir‐NO, but not Ritonavir,
could be responsible for a stronger antiproliferative potential of the NO‐modified
compound. Taken together, induction of senescent phenotype may provide an
excellent platform for developing therapeutic approaches based on selective killing of
senescent cells.",
publisher = "New Jersey: Wiley-VCH Verlag GmbH & Co",
journal = "Molecular Carcinogenesis",
title = "Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma",
number = "8",
volume = "58",
doi = "10.1002/mc.23020",
pages = "1362-1375"
}

Paskaš, S., Krajnović, T., Basile, M. S., Dunđerović, D., Cavalli, E., Mangano, K., Mammana, S., Al‐Abed, Y., Nicoletti, F., Mijatović, S.,& Maksimović-Ivanić, D.. (2019). Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma. in Molecular Carcinogenesis
New Jersey: Wiley-VCH Verlag GmbH & Co., 58(8), 1362-1375.
https://doi.org/10.1002/mc.23020

Paskaš S, Krajnović T, Basile MS, Dunđerović D, Cavalli E, Mangano K, Mammana S, Al‐Abed Y, Nicoletti F, Mijatović S, Maksimović-Ivanić D. Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma. in Molecular Carcinogenesis. 2019;58(8):1362-1375.
doi:10.1002/mc.23020 .

Paskaš, Svetlana, Krajnović, Tamara, Basile, Maria S., Dunđerović, Duško, Cavalli, Eugenio, Mangano, Katia, Mammana, Sant, Al‐Abed, Yousef, Nicoletti, Ferdinando, Mijatović, Sanja, Maksimović-Ivanić, Danijela, "Senescence as a main mechanism of Ritonavir and Ritonavir‐NO action against melanoma" in Molecular Carcinogenesis, 58, no. 8 (2019):1362-1375,
https://doi.org/10.1002/mc.23020 . .

TY  - JOUR
AU  - Maksimović-Ivanić, Danijela
AU  - Bulatović, Mirna
AU  - Edeler, David
AU  - Bensing, Christian
AU  - Golić, Igor
AU  - Korać, Aleksandra
AU  - Kaluđerović, Goran N.
AU  - Mijatović, Sanja
PY  - 2019
UR  - http://link.springer.com/10.1007/s00775-019-01640-x
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3276
AB  - Extraordinary progress in medicinal inorganic chemistry in the past few years led to the rational design of novel platinum compounds, as well as nonplatinum metal-based antitumor agents, including organotin compounds, whose activity is not based on unrepairable interaction with DNA. To overcome poor solubility and toxicity problems that limited the application of these compounds numerous delivering systems were used (Lila et al. in Biol Pharm Bull 37:206–211, 2014; Yue and Cao in Curr Cancer Drug Targets 16:480–488, 2016; Duan et al. in WIREs Nanomed Nanobiotechnol 8:776–791, 2016). Regarding high drug loading capacity, mesoporous silica nanoparticles like SBA-15 became more important for targeted drug delivery. In this study, cellular uptake and biological activities responsible for organotin(IV) compound Ph3Sn(CH2)6OH (Sn6) grafted into (3-chloropropyl)triethoxysilane functionalized SBA-15 (SBA-15p → SBA-15p|Sn6) were evaluated in human melanoma A375 cell line. Moreover, the influence of SBA-15p grafted with organotin(IV) compound on the stemness of A375 cell was tested. Given the fact that SBA-15p|Sn6 nanoparticles are nonspherical and relatively large, their internalization efficiently started even after 15 min with stable adhesion to the cell membrane. After only 2 h of incubation of A375 cells with SBA-15p|Sn6 passive fluid-phase uptake and macropinocytosis were observed. Inside of the cell, treatment with SBA-15p loaded with Sn6 promoted caspase-dependent apoptosis in parallel with senescence development. The subpopulation of cells expressing Schwann-like phenotype arose upon the treatment, while the signaling pathway responsible for maintenance of pluripotency and invasiveness, Wnt, Notch1, and Oct3/4 were modulated towards less aggressive signature. In summary, SBA-15p enhances the efficacy of free Sn6 compound through efficient uptake and well profiled intracellular response followed with decreased stem characteristics of highly invasive A375 melanoma cells.
T2  - JBIC Journal of Biological Inorganic Chemistry
T1  - The interaction between SBA-15 derivative loaded with Ph3Sn(CH2)6OH and human melanoma A375 cell line: uptake and stem phenotype loss
DO  - 10.1007/s00775-019-01640-x
ER  - 

@article{
author = "Maksimović-Ivanić, Danijela and Bulatović, Mirna and Edeler, David and Bensing, Christian and Golić, Igor and Korać, Aleksandra and Kaluđerović, Goran N. and Mijatović, Sanja",
year = "2019",
abstract = "Extraordinary progress in medicinal inorganic chemistry in the past few years led to the rational design of novel platinum compounds, as well as nonplatinum metal-based antitumor agents, including organotin compounds, whose activity is not based on unrepairable interaction with DNA. To overcome poor solubility and toxicity problems that limited the application of these compounds numerous delivering systems were used (Lila et al. in Biol Pharm Bull 37:206–211, 2014; Yue and Cao in Curr Cancer Drug Targets 16:480–488, 2016; Duan et al. in WIREs Nanomed Nanobiotechnol 8:776–791, 2016). Regarding high drug loading capacity, mesoporous silica nanoparticles like SBA-15 became more important for targeted drug delivery. In this study, cellular uptake and biological activities responsible for organotin(IV) compound Ph3Sn(CH2)6OH (Sn6) grafted into (3-chloropropyl)triethoxysilane functionalized SBA-15 (SBA-15p → SBA-15p|Sn6) were evaluated in human melanoma A375 cell line. Moreover, the influence of SBA-15p grafted with organotin(IV) compound on the stemness of A375 cell was tested. Given the fact that SBA-15p|Sn6 nanoparticles are nonspherical and relatively large, their internalization efficiently started even after 15 min with stable adhesion to the cell membrane. After only 2 h of incubation of A375 cells with SBA-15p|Sn6 passive fluid-phase uptake and macropinocytosis were observed. Inside of the cell, treatment with SBA-15p loaded with Sn6 promoted caspase-dependent apoptosis in parallel with senescence development. The subpopulation of cells expressing Schwann-like phenotype arose upon the treatment, while the signaling pathway responsible for maintenance of pluripotency and invasiveness, Wnt, Notch1, and Oct3/4 were modulated towards less aggressive signature. In summary, SBA-15p enhances the efficacy of free Sn6 compound through efficient uptake and well profiled intracellular response followed with decreased stem characteristics of highly invasive A375 melanoma cells.",
journal = "JBIC Journal of Biological Inorganic Chemistry",
title = "The interaction between SBA-15 derivative loaded with Ph3Sn(CH2)6OH and human melanoma A375 cell line: uptake and stem phenotype loss",
doi = "10.1007/s00775-019-01640-x"
}

Maksimović-Ivanić, D., Bulatović, M., Edeler, D., Bensing, C., Golić, I., Korać, A., Kaluđerović, G. N.,& Mijatović, S.. (2019). The interaction between SBA-15 derivative loaded with Ph3Sn(CH2)6OH and human melanoma A375 cell line: uptake and stem phenotype loss. in JBIC Journal of Biological Inorganic Chemistry.
https://doi.org/10.1007/s00775-019-01640-x

Maksimović-Ivanić D, Bulatović M, Edeler D, Bensing C, Golić I, Korać A, Kaluđerović GN, Mijatović S. The interaction between SBA-15 derivative loaded with Ph3Sn(CH2)6OH and human melanoma A375 cell line: uptake and stem phenotype loss. in JBIC Journal of Biological Inorganic Chemistry. 2019;.
doi:10.1007/s00775-019-01640-x .

Maksimović-Ivanić, Danijela, Bulatović, Mirna, Edeler, David, Bensing, Christian, Golić, Igor, Korać, Aleksandra, Kaluđerović, Goran N., Mijatović, Sanja, "The interaction between SBA-15 derivative loaded with Ph3Sn(CH2)6OH and human melanoma A375 cell line: uptake and stem phenotype loss" in JBIC Journal of Biological Inorganic Chemistry (2019),
https://doi.org/10.1007/s00775-019-01640-x . .

TY  - JOUR
AU  - Drača, Dijana
AU  - Mijatović, Sanja
AU  - Krajnović, Tamara
AU  - Kaluđerović, Goran N
AU  - Wessjohann, Ludger A
AU  - Maksimović-Ivanić, Danijela
PY  - 2019
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3484
UR  - http://ar.iiarjournals.org/content/39/10/5403
AB  - BACKGROUND/AIM Tubugi-1 is a more stable and accessible synthetic counterpart of natural tubulysins. This study aimed to evaluate its cytotoxic potential against anaplastic human melanoma cells. MATERIALS AND METHODS The viability of A-375 cells was determined by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet assay. The type of cell death and proliferative rate were investigated using flow cytometry and fluorescent microscopy, while the molecular background was evaluated by western blot. RESULTS Tubugi-1 reduced the viability of A-375 cells, inducing massive micronucleation, followed by augmented expression of inhibitor of nuclear factor-κB and caspase-2, typical of a mitotic catastrophe. Disturbed proliferation and G2M block with prominent caspase activity, weakened the expression of B-cell lymphoma 2 and B-cell lymphoma 2-associated X transient up-regulation, coexisted with intensive autophagy. Specific inhibition of autophagy by chloroquine resulted in conversion from mitotic catastrophe to rapid apoptosis. CONCLUSION Multilevel anticancer action of tubugi-1 is extended by co-application of an autophagy inhibitor, giving a new dimension in further preclinical advancement of this potential agent.
T2  - Anticancer Research
T1  - Synthetic Tubulysin Derivative, Tubugi-1, Against Invasive Melanoma Cells: The Cell Death Triangle.
IS  - 10
VL  - 39
DO  - 10.21873/anticanres.13734
SP  - 5403
EP  - 5415
ER  - 

@article{
author = "Drača, Dijana and Mijatović, Sanja and Krajnović, Tamara and Kaluđerović, Goran N and Wessjohann, Ludger A and Maksimović-Ivanić, Danijela",
year = "2019",
abstract = "BACKGROUND/AIM Tubugi-1 is a more stable and accessible synthetic counterpart of natural tubulysins. This study aimed to evaluate its cytotoxic potential against anaplastic human melanoma cells. MATERIALS AND METHODS The viability of A-375 cells was determined by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet assay. The type of cell death and proliferative rate were investigated using flow cytometry and fluorescent microscopy, while the molecular background was evaluated by western blot. RESULTS Tubugi-1 reduced the viability of A-375 cells, inducing massive micronucleation, followed by augmented expression of inhibitor of nuclear factor-κB and caspase-2, typical of a mitotic catastrophe. Disturbed proliferation and G2M block with prominent caspase activity, weakened the expression of B-cell lymphoma 2 and B-cell lymphoma 2-associated X transient up-regulation, coexisted with intensive autophagy. Specific inhibition of autophagy by chloroquine resulted in conversion from mitotic catastrophe to rapid apoptosis. CONCLUSION Multilevel anticancer action of tubugi-1 is extended by co-application of an autophagy inhibitor, giving a new dimension in further preclinical advancement of this potential agent.",
journal = "Anticancer Research",
title = "Synthetic Tubulysin Derivative, Tubugi-1, Against Invasive Melanoma Cells: The Cell Death Triangle.",
number = "10",
volume = "39",
doi = "10.21873/anticanres.13734",
pages = "5403-5415"
}

Drača, D., Mijatović, S., Krajnović, T., Kaluđerović, G. N., Wessjohann, L. A.,& Maksimović-Ivanić, D.. (2019). Synthetic Tubulysin Derivative, Tubugi-1, Against Invasive Melanoma Cells: The Cell Death Triangle.. in Anticancer Research, 39(10), 5403-5415.
https://doi.org/10.21873/anticanres.13734

Drača D, Mijatović S, Krajnović T, Kaluđerović GN, Wessjohann LA, Maksimović-Ivanić D. Synthetic Tubulysin Derivative, Tubugi-1, Against Invasive Melanoma Cells: The Cell Death Triangle.. in Anticancer Research. 2019;39(10):5403-5415.
doi:10.21873/anticanres.13734 .

Drača, Dijana, Mijatović, Sanja, Krajnović, Tamara, Kaluđerović, Goran N, Wessjohann, Ludger A, Maksimović-Ivanić, Danijela, "Synthetic Tubulysin Derivative, Tubugi-1, Against Invasive Melanoma Cells: The Cell Death Triangle." in Anticancer Research, 39, no. 10 (2019):5403-5415,
https://doi.org/10.21873/anticanres.13734 . .