TY  - JOUR
AU  - Stošić-Grujičić, Stanislava
AU  - Stojanović, Ivana D.
AU  - Mangano,  Katia
AU  - Fresta, Massimo
AU  - Maksimović-Ivanić, Danijela
AU  - Harhaji-Trajković, Ljubica
AU  - Popadić, Dušan
AU  - Momčilović, Miljana
AU  - Miljković, Đorđe
AU  - Kim, Joseph
AU  - Al-Abed, Yousef
AU  - Nicoletti,  Ferdinando
PY  - 2007
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3824
AB  - (S,R)-3-Phenyl-4,5-dihydro-5-isoxasole acetic acid (VGX-1027) is an isoxazole compound that exhibits various immunomodulatory properties. The capacity of VGX-1027 to prevent interleukin (IL)-1beta plus interferon-gamma-induced pancreatic islet death in vitro prompted us to evaluate its effects on the development of autoimmune diabetes in preclinical models of human type 1 diabetes mellitus (T1D). Administration of VGX-1027 to NOD mice with spontaneous or accelerated forms of diabetes induced either by injection of cyclophosphamide or by transfer of spleen cells from acutely diabetic syngeneic donors markedly reduced the cumulative incidence of diabetes and insulitis. In addition, VGX-1027 given either i.p. or p.o. to CBA/H mice made diabetic with multiple low doses of streptozotocin successfully counteracted the development of destructive insulitis and hyperglycemia. The animals receiving VGX-1027 exhibited reduced production of the proinflammatory mediators tumor necrosis factor-alpha, IL-1beta, macrophage migration inhibitory factor, and inducible nitric-oxide synthase-mediated nitric oxide generation in both pancreatic islets and peripheral compartments. These results indicate that VGX-1027 probably exerts its antidiabetogenic effects by limiting cytokine-mediated immunoinflammatory events, leading to inflammation and destruction of pancreatic islets. VGX-1027 seems worthy of being considered as a candidate drug in the development of new therapeutic strategies for the prevention and early treatment of T1D.
PB  - Rockville: American Society for Pharmacology and Experimental Therapeutics (ASPET)
T2  - Journal of Pharmacology and Experimental Therapeutics
T1  - A potent immunomodulatory compound, (S,R)-3-Phenyl-4,5-dihydro-5-isoxazole acetic acid, prevents spontaneous and accelerated forms of autoimmune diabetes in NOD mice and inhibits the immunoinflammatory diabetes induced by multiple low doses of streptozotocin in CBA/H mice
IS  - 3
VL  - 320
DO  - 10.1124/jpet.106.109272
SP  - 1038
EP  - 1049
ER  - 

@article{
author = "Stošić-Grujičić, Stanislava and Stojanović, Ivana D. and Mangano,  Katia and Fresta, Massimo and Maksimović-Ivanić, Danijela and Harhaji-Trajković, Ljubica and Popadić, Dušan and Momčilović, Miljana and Miljković, Đorđe and Kim, Joseph and Al-Abed, Yousef and Nicoletti,  Ferdinando",
year = "2007",
abstract = "(S,R)-3-Phenyl-4,5-dihydro-5-isoxasole acetic acid (VGX-1027) is an isoxazole compound that exhibits various immunomodulatory properties. The capacity of VGX-1027 to prevent interleukin (IL)-1beta plus interferon-gamma-induced pancreatic islet death in vitro prompted us to evaluate its effects on the development of autoimmune diabetes in preclinical models of human type 1 diabetes mellitus (T1D). Administration of VGX-1027 to NOD mice with spontaneous or accelerated forms of diabetes induced either by injection of cyclophosphamide or by transfer of spleen cells from acutely diabetic syngeneic donors markedly reduced the cumulative incidence of diabetes and insulitis. In addition, VGX-1027 given either i.p. or p.o. to CBA/H mice made diabetic with multiple low doses of streptozotocin successfully counteracted the development of destructive insulitis and hyperglycemia. The animals receiving VGX-1027 exhibited reduced production of the proinflammatory mediators tumor necrosis factor-alpha, IL-1beta, macrophage migration inhibitory factor, and inducible nitric-oxide synthase-mediated nitric oxide generation in both pancreatic islets and peripheral compartments. These results indicate that VGX-1027 probably exerts its antidiabetogenic effects by limiting cytokine-mediated immunoinflammatory events, leading to inflammation and destruction of pancreatic islets. VGX-1027 seems worthy of being considered as a candidate drug in the development of new therapeutic strategies for the prevention and early treatment of T1D.",
publisher = "Rockville: American Society for Pharmacology and Experimental Therapeutics (ASPET)",
journal = "Journal of Pharmacology and Experimental Therapeutics",
title = "A potent immunomodulatory compound, (S,R)-3-Phenyl-4,5-dihydro-5-isoxazole acetic acid, prevents spontaneous and accelerated forms of autoimmune diabetes in NOD mice and inhibits the immunoinflammatory diabetes induced by multiple low doses of streptozotocin in CBA/H mice",
number = "3",
volume = "320",
doi = "10.1124/jpet.106.109272",
pages = "1038-1049"
}

Stošić-Grujičić, S., Stojanović, I. D., Mangano,  ., Fresta, M., Maksimović-Ivanić, D., Harhaji-Trajković, L., Popadić, D., Momčilović, M., Miljković, Đ., Kim, J., Al-Abed, Y.,& Nicoletti,  .. (2007). A potent immunomodulatory compound, (S,R)-3-Phenyl-4,5-dihydro-5-isoxazole acetic acid, prevents spontaneous and accelerated forms of autoimmune diabetes in NOD mice and inhibits the immunoinflammatory diabetes induced by multiple low doses of streptozotocin in CBA/H mice. in Journal of Pharmacology and Experimental Therapeutics
Rockville: American Society for Pharmacology and Experimental Therapeutics (ASPET)., 320(3), 1038-1049.
https://doi.org/10.1124/jpet.106.109272

Stošić-Grujičić S, Stojanović ID, Mangano  , Fresta M, Maksimović-Ivanić D, Harhaji-Trajković L, Popadić D, Momčilović M, Miljković Đ, Kim J, Al-Abed Y, Nicoletti  . A potent immunomodulatory compound, (S,R)-3-Phenyl-4,5-dihydro-5-isoxazole acetic acid, prevents spontaneous and accelerated forms of autoimmune diabetes in NOD mice and inhibits the immunoinflammatory diabetes induced by multiple low doses of streptozotocin in CBA/H mice. in Journal of Pharmacology and Experimental Therapeutics. 2007;320(3):1038-1049.
doi:10.1124/jpet.106.109272 .

Stošić-Grujičić, Stanislava, Stojanović, Ivana D., Mangano,  Katia, Fresta, Massimo, Maksimović-Ivanić, Danijela, Harhaji-Trajković, Ljubica, Popadić, Dušan, Momčilović, Miljana, Miljković, Đorđe, Kim, Joseph, Al-Abed, Yousef, Nicoletti,  Ferdinando, "A potent immunomodulatory compound, (S,R)-3-Phenyl-4,5-dihydro-5-isoxazole acetic acid, prevents spontaneous and accelerated forms of autoimmune diabetes in NOD mice and inhibits the immunoinflammatory diabetes induced by multiple low doses of streptozotocin in CBA/H mice" in Journal of Pharmacology and Experimental Therapeutics, 320, no. 3 (2007):1038-1049,
https://doi.org/10.1124/jpet.106.109272 . .

TY  - JOUR
AU  - Harhaji-Trajković, Ljubica
AU  - Popadić, Dušan
AU  - Miljković, Đorđe
AU  - Stojanović, Ivana D.
AU  - Isaković, Aleksandra
AU  - Trajković, Vladimir
PY  - 2005
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6015
AB  - The influence of environmental pH on the production of tumoricidal free radical nitric oxide (NO) was investigated in mouse fibrosarcoma L929 and rat glioma C6 cell lines. A combination of IFN-gamma and IL-1 induced a significant NO release and subsequent reduction of cell viability in tumor cell lines. Acidification of cell culture medium reduced tumor cell NO production in a pH-dependent manner. While the inhibitory effect of acidosis on NO production in C6 cells was associated with a further decrease in cell viability, it completely rescued L929 cells from NO-dependent apoptotic and necrotic death. Acidic pH diminished IFN-gamma+ IL-1-induced expression of inducible NO synthase (iNOS) mRNA and protein, and abolished the activation of iNOS transcription factor IRF-1 in L929 cells. Moreover, extracellular acidosis significantly impaired cytokine-induced phosphorylation of MAP kinase p44/42 (ERK1/2) and subsequent expression of transcription factor c-Fos in L929 cells. Finally, mild acidosis (pH 6.8) augmented, while severe acidosis (pH 6.0) reduced, IFN-gamma-induced iNOS activation/NO release and NO-dependent anticancer activity of rat and mouse macrophages. Taken together, our findings indicate that modulation of macrophage and tumor cell iNOS by an acidic microenvironment might influence the progression of NO-sensitive solid tumors.
PB  - Elsevier Inc.
T2  - Free Radical Biology and Medicine
T1  - Acidosis affects tumor cell survival through modulation of nitric oxide release
IS  - 2
VL  - 40
DO  - 10.1016/j.freeradbiomed.2005.08.027
SP  - 226
EP  - 235
ER  - 

@article{
author = "Harhaji-Trajković, Ljubica and Popadić, Dušan and Miljković, Đorđe and Stojanović, Ivana D. and Isaković, Aleksandra and Trajković, Vladimir",
year = "2005",
abstract = "The influence of environmental pH on the production of tumoricidal free radical nitric oxide (NO) was investigated in mouse fibrosarcoma L929 and rat glioma C6 cell lines. A combination of IFN-gamma and IL-1 induced a significant NO release and subsequent reduction of cell viability in tumor cell lines. Acidification of cell culture medium reduced tumor cell NO production in a pH-dependent manner. While the inhibitory effect of acidosis on NO production in C6 cells was associated with a further decrease in cell viability, it completely rescued L929 cells from NO-dependent apoptotic and necrotic death. Acidic pH diminished IFN-gamma+ IL-1-induced expression of inducible NO synthase (iNOS) mRNA and protein, and abolished the activation of iNOS transcription factor IRF-1 in L929 cells. Moreover, extracellular acidosis significantly impaired cytokine-induced phosphorylation of MAP kinase p44/42 (ERK1/2) and subsequent expression of transcription factor c-Fos in L929 cells. Finally, mild acidosis (pH 6.8) augmented, while severe acidosis (pH 6.0) reduced, IFN-gamma-induced iNOS activation/NO release and NO-dependent anticancer activity of rat and mouse macrophages. Taken together, our findings indicate that modulation of macrophage and tumor cell iNOS by an acidic microenvironment might influence the progression of NO-sensitive solid tumors.",
publisher = "Elsevier Inc.",
journal = "Free Radical Biology and Medicine",
title = "Acidosis affects tumor cell survival through modulation of nitric oxide release",
number = "2",
volume = "40",
doi = "10.1016/j.freeradbiomed.2005.08.027",
pages = "226-235"
}

Harhaji-Trajković, L., Popadić, D., Miljković, Đ., Stojanović, I. D., Isaković, A.,& Trajković, V.. (2005). Acidosis affects tumor cell survival through modulation of nitric oxide release. in Free Radical Biology and Medicine
Elsevier Inc.., 40(2), 226-235.
https://doi.org/10.1016/j.freeradbiomed.2005.08.027

Harhaji-Trajković L, Popadić D, Miljković Đ, Stojanović ID, Isaković A, Trajković V. Acidosis affects tumor cell survival through modulation of nitric oxide release. in Free Radical Biology and Medicine. 2005;40(2):226-235.
doi:10.1016/j.freeradbiomed.2005.08.027 .

Harhaji-Trajković, Ljubica, Popadić, Dušan, Miljković, Đorđe, Stojanović, Ivana D., Isaković, Aleksandra, Trajković, Vladimir, "Acidosis affects tumor cell survival through modulation of nitric oxide release" in Free Radical Biology and Medicine, 40, no. 2 (2005):226-235,
https://doi.org/10.1016/j.freeradbiomed.2005.08.027 . .

TY  - JOUR
AU  - Trajković, Vladimir
AU  - Marković, Miloš
AU  - Samardzić, Tatjana
AU  - Miljković, Đorđe
AU  - Popadić, Dušan
AU  - Mostarica Stojković, Marija
PY  - 2001
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5996
AB  - Because the neurotoxic effects of the antifungal drug amphotericin B
(AMB) closely resemble those ascribed to the highly reactive gaseous free radical nitric
oxide (NO), we investigated the effect of AMB on NO production in rodent astrocytes.
AMB caused a dose-dependent increase of NO generation in interferon-g (IFN-g)-stimulated rat and mouse astrocytes, as well as in IFN-g 1 tumor necrosis factor-a (TNFa)-activated rat astrocytoma cell line C6. Treatment of rat astrocytes with AMB markedly potentiated IFN-g-triggered expression of mRNA for iNOS, but not for its
transcription factor IRF-1. The activation of transcription factor NF-kB was apparently
required for AMB-induced iNOS mRNA expression, as the latter was abolished by
NF-kB inhibitors: pyrrolidine dithiocarbamate and MG132. AMB-mediated enhancement of astrocyte NO production was partly dependent on endogenous IL-1, as shown by
partial inhibition of AMB effect with IL-1 receptor antagonist. IFN-g 1 AMB treatment
led to reduction of astrocyte mitochondrial respiration (measured by MTT assay) that
has been completely reverted by selective iNOS inhibitor aminoguanidine. AMB toxicity
toward IFN-g-stimulated astrocytes was dependent on both AMB and NO action, since
AMB and NO-releasing substance SNP synergized in inducing astrocyte mitochondrial
dysfunction. These results suggest that the enhancement of cytokine-induced iNOS
activation in astrocytes and the subsequent release of high amounts of NO might be at
least partly responsible for AMB neurotoxicity.
PB  - Hoboken: Wiley
T2  - Glia
T1  - Amphotericin B Potentiates the Activation of Inducible Nitric Oxide Synthase and Causes Nitric OxideDependent Mitochondrial Dysfunction in Cytokine-Treated Rodent Astrocytes
IS  - 3
VL  - 35
DO  - 10.1002/glia.1083
SP  - 180
EP  - 188
ER  - 

@article{
author = "Trajković, Vladimir and Marković, Miloš and Samardzić, Tatjana and Miljković, Đorđe and Popadić, Dušan and Mostarica Stojković, Marija",
year = "2001",
abstract = "Because the neurotoxic effects of the antifungal drug amphotericin B
(AMB) closely resemble those ascribed to the highly reactive gaseous free radical nitric
oxide (NO), we investigated the effect of AMB on NO production in rodent astrocytes.
AMB caused a dose-dependent increase of NO generation in interferon-g (IFN-g)-stimulated rat and mouse astrocytes, as well as in IFN-g 1 tumor necrosis factor-a (TNFa)-activated rat astrocytoma cell line C6. Treatment of rat astrocytes with AMB markedly potentiated IFN-g-triggered expression of mRNA for iNOS, but not for its
transcription factor IRF-1. The activation of transcription factor NF-kB was apparently
required for AMB-induced iNOS mRNA expression, as the latter was abolished by
NF-kB inhibitors: pyrrolidine dithiocarbamate and MG132. AMB-mediated enhancement of astrocyte NO production was partly dependent on endogenous IL-1, as shown by
partial inhibition of AMB effect with IL-1 receptor antagonist. IFN-g 1 AMB treatment
led to reduction of astrocyte mitochondrial respiration (measured by MTT assay) that
has been completely reverted by selective iNOS inhibitor aminoguanidine. AMB toxicity
toward IFN-g-stimulated astrocytes was dependent on both AMB and NO action, since
AMB and NO-releasing substance SNP synergized in inducing astrocyte mitochondrial
dysfunction. These results suggest that the enhancement of cytokine-induced iNOS
activation in astrocytes and the subsequent release of high amounts of NO might be at
least partly responsible for AMB neurotoxicity.",
publisher = "Hoboken: Wiley",
journal = "Glia",
title = "Amphotericin B Potentiates the Activation of Inducible Nitric Oxide Synthase and Causes Nitric OxideDependent Mitochondrial Dysfunction in Cytokine-Treated Rodent Astrocytes",
number = "3",
volume = "35",
doi = "10.1002/glia.1083",
pages = "180-188"
}

Trajković, V., Marković, M., Samardzić, T., Miljković, Đ., Popadić, D.,& Mostarica Stojković, M.. (2001). Amphotericin B Potentiates the Activation of Inducible Nitric Oxide Synthase and Causes Nitric OxideDependent Mitochondrial Dysfunction in Cytokine-Treated Rodent Astrocytes. in Glia
Hoboken: Wiley., 35(3), 180-188.
https://doi.org/10.1002/glia.1083

Trajković V, Marković M, Samardzić T, Miljković Đ, Popadić D, Mostarica Stojković M. Amphotericin B Potentiates the Activation of Inducible Nitric Oxide Synthase and Causes Nitric OxideDependent Mitochondrial Dysfunction in Cytokine-Treated Rodent Astrocytes. in Glia. 2001;35(3):180-188.
doi:10.1002/glia.1083 .

Trajković, Vladimir, Marković, Miloš, Samardzić, Tatjana, Miljković, Đorđe, Popadić, Dušan, Mostarica Stojković, Marija, "Amphotericin B Potentiates the Activation of Inducible Nitric Oxide Synthase and Causes Nitric OxideDependent Mitochondrial Dysfunction in Cytokine-Treated Rodent Astrocytes" in Glia, 35, no. 3 (2001):180-188,
https://doi.org/10.1002/glia.1083 . .