TY  - JOUR
AU  - Todorović, Nevena
AU  - Tomanović, Nada
AU  - Gass, Peter
AU  - Filipović, Dragana
PY  - 2016
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/883
AB  - Olanzapine, an atypical antipsychotic, is efficient in stress associated psychiatric diseases, but its effect on the liver, a primary organ for drug activation and detoxification, still remains unclear. The effect of olanzapine administration (7.5 mg/kg/day), on rat hepatic glutathione (GSH)-dependent defense and proinflammatory cytokines following 6 weeks of chronic social isolation (CSIS), which causes depressive-and anxiety-like behavior in adult male Wistar rats, was investigated. The subcellular distribution of nuclear factor-kappa B (NF-kappa B), cytosolic inducible nitric oxide synthase (iNOS) protein levels and hepatic histological alterations were also determined. Decreased GSH content and glutathione reductase activity associated with increased catalase and glutathione S-transferase activity following CSIS indicated hepatic oxidative stress. Moreover, CSIS caused NF-kappa B nuclear translocation and the concomitant increase in iNOS together with increase in interleukin-1beta and tumor necrosis factor alpha protein levels, but no effect on interleukin-6. Olanzapine treatment suppressed NF-kappa B activation and iNOS expression and caused modulation of GSH-dependent defense systems but failed to reverse CSIS-induced increase in hepatic proinflammatory cytokines. Portal inflammation, focal hepatocyte necrosis and an increased number of Kupffer cells in CSIS rats (vehicle-or olanzapine-treated) were found. Olanzapine-treated socially reared rats showed portal inflammation and focal hepatocyte necrosis. Data suggest that CSIS compromised GSH-dependent defense, triggered a proinflammatory response and histological alterations in rat liver. Olanzapine treatment partially reversed the alterations in hepatic GSH-dependent defense, but showed no anti-inflammatory effect suggesting that it may provide protective effect against hepatic CSIS-induced oxidative stress, but not against inflammation. (C) 2015 Elsevier B.V. All rights reserved.
PB  - Elsevier
T2  - European Journal of Pharmaceutical Sciences
T1  - Olanzapine modulation of hepatic oxidative stress and inflammation in socially isolated rats
VL  - 81
SP  - 94
EP  - 102
DO  - 10.1016/j.ejps.2015.10.010
ER  - 

@article{
author = "Todorović, Nevena and Tomanović, Nada and Gass, Peter and Filipović, Dragana",
year = "2016",
abstract = "Olanzapine, an atypical antipsychotic, is efficient in stress associated psychiatric diseases, but its effect on the liver, a primary organ for drug activation and detoxification, still remains unclear. The effect of olanzapine administration (7.5 mg/kg/day), on rat hepatic glutathione (GSH)-dependent defense and proinflammatory cytokines following 6 weeks of chronic social isolation (CSIS), which causes depressive-and anxiety-like behavior in adult male Wistar rats, was investigated. The subcellular distribution of nuclear factor-kappa B (NF-kappa B), cytosolic inducible nitric oxide synthase (iNOS) protein levels and hepatic histological alterations were also determined. Decreased GSH content and glutathione reductase activity associated with increased catalase and glutathione S-transferase activity following CSIS indicated hepatic oxidative stress. Moreover, CSIS caused NF-kappa B nuclear translocation and the concomitant increase in iNOS together with increase in interleukin-1beta and tumor necrosis factor alpha protein levels, but no effect on interleukin-6. Olanzapine treatment suppressed NF-kappa B activation and iNOS expression and caused modulation of GSH-dependent defense systems but failed to reverse CSIS-induced increase in hepatic proinflammatory cytokines. Portal inflammation, focal hepatocyte necrosis and an increased number of Kupffer cells in CSIS rats (vehicle-or olanzapine-treated) were found. Olanzapine-treated socially reared rats showed portal inflammation and focal hepatocyte necrosis. Data suggest that CSIS compromised GSH-dependent defense, triggered a proinflammatory response and histological alterations in rat liver. Olanzapine treatment partially reversed the alterations in hepatic GSH-dependent defense, but showed no anti-inflammatory effect suggesting that it may provide protective effect against hepatic CSIS-induced oxidative stress, but not against inflammation. (C) 2015 Elsevier B.V. All rights reserved.",
publisher = "Elsevier",
journal = "European Journal of Pharmaceutical Sciences",
title = "Olanzapine modulation of hepatic oxidative stress and inflammation in socially isolated rats",
volume = "81",
pages = "94-102",
doi = "10.1016/j.ejps.2015.10.010"
}

Todorović, N., Tomanović, N., Gass, P.,& Filipović, D.. (2016). Olanzapine modulation of hepatic oxidative stress and inflammation in socially isolated rats. in European Journal of Pharmaceutical Sciences
Elsevier., 81, 94-102.
https://doi.org/10.1016/j.ejps.2015.10.010

Todorović N, Tomanović N, Gass P, Filipović D. Olanzapine modulation of hepatic oxidative stress and inflammation in socially isolated rats. in European Journal of Pharmaceutical Sciences. 2016;81:94-102.
doi:10.1016/j.ejps.2015.10.010 .

Todorović, Nevena, Tomanović, Nada, Gass, Peter, Filipović, Dragana, "Olanzapine modulation of hepatic oxidative stress and inflammation in socially isolated rats" in European Journal of Pharmaceutical Sciences, 81 (2016):94-102,
https://doi.org/10.1016/j.ejps.2015.10.010 . .

TY  - JOUR
AU  - Jotić, Ana
AU  - Ješić, Snežana
AU  - Živković, Maja
AU  - Tomanović, Nada
AU  - Kuveljić, Jovana
AU  - Stanković, Aleksandra
PY  - 2015
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/679
AB  - Objective: Toll-like receptors (TLRs) have a prominent role in inducing innate immune response. It has been suggested that regulation of TLRs is involved in the pathogenesis of chronic otitis media. TLR 2 and TLR 4 polymorphisms were connected with susceptibility to acute otitis and chronic otitis with effusion. The objective of this study was to establish expression of TLR 2 and 4 on middle ear mucosa in different types of chronic suppurative otitis media (CSOM), and the influence of gene polymorphisms TLR 2 Arg753Gln and TLR 4 Thr399Ile and Asp299Gly to susceptibility to CSOM. Material and methods: Middle ear mucosa and full blood samples were obtained from 85 patients With chronic suppurative otitis media with and without cholesteatoma. Control group for mucosal TLR expression consisted of 71 samples of middle ear mucosa taken from patients with otosclerosis, and control group for DNA polymorphism consisted of 100 full blood samples in healthy subjects. DNA polymorphism detection was done with restriction fragment length polymorphism in RI PCR. Expression of TLR 2 and 4 was determined with immunohistochemical staining. Results: TLR 2 and TLR 4 expression on the middle ear mucosa was not influenced by age of the patients with chronic otitis media. Incidence of TLR 2 Arg753Gln polymorphism was significantly higher in patients with chronic otitis media, compared to control group. Significant association between TLR 2 Arg753Gln polymorphism and different types of mucosal changes in patients with chronic otitis media was established. TLR 2 and 4 expression on experimental group mucosa was significantly different compared to control group, where there was no expression (p = 0.000). Strong dependence of TLR 2 and TLR 4 expression on middle ear mucosa with different mucosal changes and immunohistochemical activity after staining was detected. Conclusion: Certain polymorphisms in TLR genes could be indicative for susceptibility to chronic otitis media. Expression of TLR 2 and 4 on middle ear mucosa was more dependable on different types of mucosal changes and type of CSOM than on bacteria found in the specimens. This can indicate that the type of mucosal changes are closely correlated with TLRs activity in middle ear. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
T2  - Auris Nasus Larynx
T1  - Polymorphisms in Toll-like receptors 2 and 4 genes and their expression in chronic suppurative otitis media
VL  - 42
IS  - 6
SP  - 431
EP  - 437
DO  - 10.1016/j.anl.2015.04.010
ER  - 

@article{
author = "Jotić, Ana and Ješić, Snežana and Živković, Maja and Tomanović, Nada and Kuveljić, Jovana and Stanković, Aleksandra",
year = "2015",
abstract = "Objective: Toll-like receptors (TLRs) have a prominent role in inducing innate immune response. It has been suggested that regulation of TLRs is involved in the pathogenesis of chronic otitis media. TLR 2 and TLR 4 polymorphisms were connected with susceptibility to acute otitis and chronic otitis with effusion. The objective of this study was to establish expression of TLR 2 and 4 on middle ear mucosa in different types of chronic suppurative otitis media (CSOM), and the influence of gene polymorphisms TLR 2 Arg753Gln and TLR 4 Thr399Ile and Asp299Gly to susceptibility to CSOM. Material and methods: Middle ear mucosa and full blood samples were obtained from 85 patients With chronic suppurative otitis media with and without cholesteatoma. Control group for mucosal TLR expression consisted of 71 samples of middle ear mucosa taken from patients with otosclerosis, and control group for DNA polymorphism consisted of 100 full blood samples in healthy subjects. DNA polymorphism detection was done with restriction fragment length polymorphism in RI PCR. Expression of TLR 2 and 4 was determined with immunohistochemical staining. Results: TLR 2 and TLR 4 expression on the middle ear mucosa was not influenced by age of the patients with chronic otitis media. Incidence of TLR 2 Arg753Gln polymorphism was significantly higher in patients with chronic otitis media, compared to control group. Significant association between TLR 2 Arg753Gln polymorphism and different types of mucosal changes in patients with chronic otitis media was established. TLR 2 and 4 expression on experimental group mucosa was significantly different compared to control group, where there was no expression (p = 0.000). Strong dependence of TLR 2 and TLR 4 expression on middle ear mucosa with different mucosal changes and immunohistochemical activity after staining was detected. Conclusion: Certain polymorphisms in TLR genes could be indicative for susceptibility to chronic otitis media. Expression of TLR 2 and 4 on middle ear mucosa was more dependable on different types of mucosal changes and type of CSOM than on bacteria found in the specimens. This can indicate that the type of mucosal changes are closely correlated with TLRs activity in middle ear. (C) 2015 Elsevier Ireland Ltd. All rights reserved.",
journal = "Auris Nasus Larynx",
title = "Polymorphisms in Toll-like receptors 2 and 4 genes and their expression in chronic suppurative otitis media",
volume = "42",
number = "6",
pages = "431-437",
doi = "10.1016/j.anl.2015.04.010"
}

Jotić, A., Ješić, S., Živković, M., Tomanović, N., Kuveljić, J.,& Stanković, A.. (2015). Polymorphisms in Toll-like receptors 2 and 4 genes and their expression in chronic suppurative otitis media. in Auris Nasus Larynx, 42(6), 431-437.
https://doi.org/10.1016/j.anl.2015.04.010

Jotić A, Ješić S, Živković M, Tomanović N, Kuveljić J, Stanković A. Polymorphisms in Toll-like receptors 2 and 4 genes and their expression in chronic suppurative otitis media. in Auris Nasus Larynx. 2015;42(6):431-437.
doi:10.1016/j.anl.2015.04.010 .

Jotić, Ana, Ješić, Snežana, Živković, Maja, Tomanović, Nada, Kuveljić, Jovana, Stanković, Aleksandra, "Polymorphisms in Toll-like receptors 2 and 4 genes and their expression in chronic suppurative otitis media" in Auris Nasus Larynx, 42, no. 6 (2015):431-437,
https://doi.org/10.1016/j.anl.2015.04.010 . .

TY  - JOUR
AU  - Ješić, Snežana
AU  - Jotić, Ana
AU  - Tomanović, Nada
AU  - Živković, Maja
AU  - Kolaković, Ana
AU  - Stanković, Aleksandra
PY  - 2014
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/6051
AB  - Objectives: The objectives were to detect and compare the expression of toll-like receptors (TLRs) 2, 4 and nuclear factor kappa B in mucosal lesions of chronic otitis. Methods: Fifty-five tissue samples obtained from children and adults operated on for otitis were investigated by semiquantitative immunohistochemical methods using polyclonal antibodies for TLR 2, 4 and NFkB. Kruskal-Wallis, Mann-Whitney, and Kendalls tau rank correlation tests were used. Results: Stronger expression of TLR2, 4 was found in inflamed mucosa than in the control for children and adults (TLR2: H = 23.86, P LT .001; TLR4: H = 22.80, P LT .001) (TLR2: H = 17.53, P LT .001; TLR4: H = 11.99, P LT .001); in cholesteatoma perimatrix compared to tubotympanic lesions in children (TLR2: H = 11.06, P = .004; TLR4: H = 10.61, P = .005) and adults (TLR2: H = 10.73, P =.013; TLR4: H = 9.65, P = .021). No differences were found in NFkB expression (H = 0.042, P = .99). Significant correlations were found for all pairs of molecules in cholesteatoma and tubotympanic mucosa of adults (TLR2, 4: P = .002, P LT .001; TLR2-NfkB: P = .032, P = .021; TLR4-NFkB: P =.035, P = .0013), only TLR4-NFkB in tubotympanic otitis of children (P = .026). Conclusions: Toll-like receptors 2, 4 and NFkB mediate inflammation in cholesteatoma and mucosal lesions of tubotympanic otitis in children and adults. Significant correlations between all pairs of molecules in all samples were detected in adults, but only TLR4-NFkB in children.
T2  - Annals of Otology Rhinology and Laryngology
T1  - Expression of Toll-Like Receptors 2, 4 and Nuclear Factor Kappa B in Mucosal Lesions of Human Otitis: Pattern and Relationship in a Clinical Immunohistochemical Study
VL  - 123
IS  - 6
SP  - 434
EP  - 441
DO  - 10.1177/0003489414527229
ER  - 

@article{
author = "Ješić, Snežana and Jotić, Ana and Tomanović, Nada and Živković, Maja and Kolaković, Ana and Stanković, Aleksandra",
year = "2014",
abstract = "Objectives: The objectives were to detect and compare the expression of toll-like receptors (TLRs) 2, 4 and nuclear factor kappa B in mucosal lesions of chronic otitis. Methods: Fifty-five tissue samples obtained from children and adults operated on for otitis were investigated by semiquantitative immunohistochemical methods using polyclonal antibodies for TLR 2, 4 and NFkB. Kruskal-Wallis, Mann-Whitney, and Kendalls tau rank correlation tests were used. Results: Stronger expression of TLR2, 4 was found in inflamed mucosa than in the control for children and adults (TLR2: H = 23.86, P LT .001; TLR4: H = 22.80, P LT .001) (TLR2: H = 17.53, P LT .001; TLR4: H = 11.99, P LT .001); in cholesteatoma perimatrix compared to tubotympanic lesions in children (TLR2: H = 11.06, P = .004; TLR4: H = 10.61, P = .005) and adults (TLR2: H = 10.73, P =.013; TLR4: H = 9.65, P = .021). No differences were found in NFkB expression (H = 0.042, P = .99). Significant correlations were found for all pairs of molecules in cholesteatoma and tubotympanic mucosa of adults (TLR2, 4: P = .002, P LT .001; TLR2-NfkB: P = .032, P = .021; TLR4-NFkB: P =.035, P = .0013), only TLR4-NFkB in tubotympanic otitis of children (P = .026). Conclusions: Toll-like receptors 2, 4 and NFkB mediate inflammation in cholesteatoma and mucosal lesions of tubotympanic otitis in children and adults. Significant correlations between all pairs of molecules in all samples were detected in adults, but only TLR4-NFkB in children.",
journal = "Annals of Otology Rhinology and Laryngology",
title = "Expression of Toll-Like Receptors 2, 4 and Nuclear Factor Kappa B in Mucosal Lesions of Human Otitis: Pattern and Relationship in a Clinical Immunohistochemical Study",
volume = "123",
number = "6",
pages = "434-441",
doi = "10.1177/0003489414527229"
}

Ješić, S., Jotić, A., Tomanović, N., Živković, M., Kolaković, A.,& Stanković, A.. (2014). Expression of Toll-Like Receptors 2, 4 and Nuclear Factor Kappa B in Mucosal Lesions of Human Otitis: Pattern and Relationship in a Clinical Immunohistochemical Study. in Annals of Otology Rhinology and Laryngology, 123(6), 434-441.
https://doi.org/10.1177/0003489414527229

Ješić S, Jotić A, Tomanović N, Živković M, Kolaković A, Stanković A. Expression of Toll-Like Receptors 2, 4 and Nuclear Factor Kappa B in Mucosal Lesions of Human Otitis: Pattern and Relationship in a Clinical Immunohistochemical Study. in Annals of Otology Rhinology and Laryngology. 2014;123(6):434-441.
doi:10.1177/0003489414527229 .

Ješić, Snežana, Jotić, Ana, Tomanović, Nada, Živković, Maja, Kolaković, Ana, Stanković, Aleksandra, "Expression of Toll-Like Receptors 2, 4 and Nuclear Factor Kappa B in Mucosal Lesions of Human Otitis: Pattern and Relationship in a Clinical Immunohistochemical Study" in Annals of Otology Rhinology and Laryngology, 123, no. 6 (2014):434-441,
https://doi.org/10.1177/0003489414527229 . .

TY  - JOUR
AU  - Martinović, Jelena
AU  - Todorović, Nevena
AU  - Tomanović, Nada
AU  - Bošković, Maja
AU  - Djordjevic, Snezana
AU  - Lazarević-Pašti, Tamara
AU  - Bernardi, Rick E.
AU  - Đurđević, Aleksandra
AU  - Filipović, Dragana
PY  - 2014
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/6043
AB  - Chronic exposure to stress contributes to the etiology of mood disorders, and the liver as a target organ of antidepressant and antipsychotic drug metabolism is vulnerable to drug-induced toxicity. We investigated the effects of chronic administration of fluoxetine (15 mg/kg/day) or clozapine (20 mg/kg/day) on liver injury via the measurement of liver enzymes, oxidative stress and histopathology in rats exposed to chronic social isolation (21 days), an animal model of depression, and controls. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the liver content of carbonyl groups, malonyldialdehyde (MDA), reduced glutathione (GSH), cytosolic glutathione S-transferase (GST) and nitric oxide (NO) metabolites were determined. We also characterized nuclear factor-kappa B (NF-kappa B), cyclooxygenase-2 (COX-2) and CuZn-superoxide dismutase (CuZnSOD) protein expression as well as histopathological changes. Increased serum ALT activity in chronically-isolated and control animals treated with both drugs was found while increased AST activity was observed only in fluoxetine-treated rats (chronically-isolated and controls). Increased carbonyl content, MDA, GST activity and decreased GSH levels in drug-treated controls/chronically-isolated animals suggest a link between drugs and hepatic oxidative stress. Increased NO levels associated with NF-kappa B activation and the concomitant increased COX-2 expression together with compromised CuZnSOD expression in clozapine-treated chronically-isolated rats likely reinforce oxidative stress, observed by increased lipid peroxidation and GSH depletion. In contrast, fluoxetine reduced NO levels in chronically-isolated rats. Isolation induced oxidative stress but histological changes were similar to those observed in vehicle-treated controls. Chronic administration of fluoxetine in both chronically-isolated and control animals resulted in more or less normal hepatic architecture, while clozapine in both groups resulted in liver injury. These data suggest that clozapine appears to have a higher potential to induce liver toxicity than fluoxetine. (C) 2014 Elsevier B.V. All rights reserved.
T2  - European Journal of Pharmaceutical Sciences
T1  - Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: A histopathological study
VL  - 59
SP  - 20
EP  - 30
DO  - 10.1016/j.ejps.2014.04.010
ER  - 

@article{
author = "Martinović, Jelena and Todorović, Nevena and Tomanović, Nada and Bošković, Maja and Djordjevic, Snezana and Lazarević-Pašti, Tamara and Bernardi, Rick E. and Đurđević, Aleksandra and Filipović, Dragana",
year = "2014",
abstract = "Chronic exposure to stress contributes to the etiology of mood disorders, and the liver as a target organ of antidepressant and antipsychotic drug metabolism is vulnerable to drug-induced toxicity. We investigated the effects of chronic administration of fluoxetine (15 mg/kg/day) or clozapine (20 mg/kg/day) on liver injury via the measurement of liver enzymes, oxidative stress and histopathology in rats exposed to chronic social isolation (21 days), an animal model of depression, and controls. The activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), the liver content of carbonyl groups, malonyldialdehyde (MDA), reduced glutathione (GSH), cytosolic glutathione S-transferase (GST) and nitric oxide (NO) metabolites were determined. We also characterized nuclear factor-kappa B (NF-kappa B), cyclooxygenase-2 (COX-2) and CuZn-superoxide dismutase (CuZnSOD) protein expression as well as histopathological changes. Increased serum ALT activity in chronically-isolated and control animals treated with both drugs was found while increased AST activity was observed only in fluoxetine-treated rats (chronically-isolated and controls). Increased carbonyl content, MDA, GST activity and decreased GSH levels in drug-treated controls/chronically-isolated animals suggest a link between drugs and hepatic oxidative stress. Increased NO levels associated with NF-kappa B activation and the concomitant increased COX-2 expression together with compromised CuZnSOD expression in clozapine-treated chronically-isolated rats likely reinforce oxidative stress, observed by increased lipid peroxidation and GSH depletion. In contrast, fluoxetine reduced NO levels in chronically-isolated rats. Isolation induced oxidative stress but histological changes were similar to those observed in vehicle-treated controls. Chronic administration of fluoxetine in both chronically-isolated and control animals resulted in more or less normal hepatic architecture, while clozapine in both groups resulted in liver injury. These data suggest that clozapine appears to have a higher potential to induce liver toxicity than fluoxetine. (C) 2014 Elsevier B.V. All rights reserved.",
journal = "European Journal of Pharmaceutical Sciences",
title = "Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: A histopathological study",
volume = "59",
pages = "20-30",
doi = "10.1016/j.ejps.2014.04.010"
}

Martinović, J., Todorović, N., Tomanović, N., Bošković, M., Djordjevic, S., Lazarević-Pašti, T., Bernardi, R. E., Đurđević, A.,& Filipović, D.. (2014). Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: A histopathological study. in European Journal of Pharmaceutical Sciences, 59, 20-30.
https://doi.org/10.1016/j.ejps.2014.04.010

Martinović J, Todorović N, Tomanović N, Bošković M, Djordjevic S, Lazarević-Pašti T, Bernardi RE, Đurđević A, Filipović D. Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: A histopathological study. in European Journal of Pharmaceutical Sciences. 2014;59:20-30.
doi:10.1016/j.ejps.2014.04.010 .

Martinović, Jelena, Todorović, Nevena, Tomanović, Nada, Bošković, Maja, Djordjevic, Snezana, Lazarević-Pašti, Tamara, Bernardi, Rick E., Đurđević, Aleksandra, Filipović, Dragana, "Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: A histopathological study" in European Journal of Pharmaceutical Sciences, 59 (2014):20-30,
https://doi.org/10.1016/j.ejps.2014.04.010 . .