TY  - JOUR
AU  - Chrienova, Zofia
AU  - Rysanek, David
AU  - Novak, Josef
AU  - Vasicova, Pavla
AU  - Oleksak, Patrik
AU  - Andrys, Rudolf
AU  - Skarka, Adam
AU  - Dumanović, Jelena
AU  - Milovanović, Zoran
AU  - Jaćević, Vesna
AU  - Chvojkova, Marketa
AU  - Holubova, Kristina
AU  - Vales, Karel
AU  - Skoupilova, Veronika
AU  - Valko, Marian
AU  - Jomova, Klaudia
AU  - Alomar, Suliman Y.
AU  - Botelho, Fernanda D.
AU  - Franca, Tanos C. C.
AU  - Kuca, Kamil
AU  - Hodny, Zdenek
AU  - Nepovimova, Eugenie
PY  - 2023
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/6376
AB  - Frentizole is immunosuppressive drug with low acute toxicity and lifespan-prolonging effect. Recently, frentizole´s potential to disrupt toxic amyloid β (Aβ) - Aβ-binding alcohol dehydrogenase (ABAD) interaction in mitochondria in Alzheimer´s brains has been revealed. Another broadly studied drug with anti-aging and immunosuppressive properties is an mTOR inhibitor – rapamycin. Since we do not yet precisely know what is behind the lifespan-prolonging effect of rapamycin and frentizole, whether it is the ability to inhibit the mTOR signaling pathway, reduction in mitochondrial toxicity, immunosuppressive effect, or a combination of all of them, we have decided within our previous work to dock the entire in-house library of almost 240 Aβ-ABAD modulators into the FKBP-rapamycin-binding (FRB) domain of mTOR in order to interlink mTOR-centric and mitochondrial free radical-centric theories of aging and thus to increase the chances of success. Based on the results of the docking study, molecular dynamic simulation and MM-PBSA calculations, we have selected nine frentizole-like compounds (1 – 9). Subsequently, we have determined their real physical-chemical properties (logP, logD, pKa and solubility in water and buffer), cytotoxic/cytostatic, mTOR inhibitory, and in vitro anti-senescence (senolytic and senomorphic) effects. Finally, the three best candidates (4, 8, and 9) have been forwarded for in vivo safety studies to assess their acute toxicity and pharmacokinetic properties. Based on obtained results, only compound 4 demonstrated the best results within in vitro testing, the ability to cross the blood-brain barrier and the lowest acute toxicity (LD50 in male mice 559 mg/kg; LD50 in female mice 575 mg/kg).
PB  - Elsevier
T2  - Biomedicine & Pharmacotherapy
T1  - Frentizole derivatives with mTOR inhibiting and senomorphic properties
VL  - 167
SP  - 115600
DO  - 10.1016/j.biopha.2023.115600
ER  - 

@article{
author = "Chrienova, Zofia and Rysanek, David and Novak, Josef and Vasicova, Pavla and Oleksak, Patrik and Andrys, Rudolf and Skarka, Adam and Dumanović, Jelena and Milovanović, Zoran and Jaćević, Vesna and Chvojkova, Marketa and Holubova, Kristina and Vales, Karel and Skoupilova, Veronika and Valko, Marian and Jomova, Klaudia and Alomar, Suliman Y. and Botelho, Fernanda D. and Franca, Tanos C. C. and Kuca, Kamil and Hodny, Zdenek and Nepovimova, Eugenie",
year = "2023",
abstract = "Frentizole is immunosuppressive drug with low acute toxicity and lifespan-prolonging effect. Recently, frentizole´s potential to disrupt toxic amyloid β (Aβ) - Aβ-binding alcohol dehydrogenase (ABAD) interaction in mitochondria in Alzheimer´s brains has been revealed. Another broadly studied drug with anti-aging and immunosuppressive properties is an mTOR inhibitor – rapamycin. Since we do not yet precisely know what is behind the lifespan-prolonging effect of rapamycin and frentizole, whether it is the ability to inhibit the mTOR signaling pathway, reduction in mitochondrial toxicity, immunosuppressive effect, or a combination of all of them, we have decided within our previous work to dock the entire in-house library of almost 240 Aβ-ABAD modulators into the FKBP-rapamycin-binding (FRB) domain of mTOR in order to interlink mTOR-centric and mitochondrial free radical-centric theories of aging and thus to increase the chances of success. Based on the results of the docking study, molecular dynamic simulation and MM-PBSA calculations, we have selected nine frentizole-like compounds (1 – 9). Subsequently, we have determined their real physical-chemical properties (logP, logD, pKa and solubility in water and buffer), cytotoxic/cytostatic, mTOR inhibitory, and in vitro anti-senescence (senolytic and senomorphic) effects. Finally, the three best candidates (4, 8, and 9) have been forwarded for in vivo safety studies to assess their acute toxicity and pharmacokinetic properties. Based on obtained results, only compound 4 demonstrated the best results within in vitro testing, the ability to cross the blood-brain barrier and the lowest acute toxicity (LD50 in male mice 559 mg/kg; LD50 in female mice 575 mg/kg).",
publisher = "Elsevier",
journal = "Biomedicine & Pharmacotherapy",
title = "Frentizole derivatives with mTOR inhibiting and senomorphic properties",
volume = "167",
pages = "115600",
doi = "10.1016/j.biopha.2023.115600"
}

Chrienova, Z., Rysanek, D., Novak, J., Vasicova, P., Oleksak, P., Andrys, R., Skarka, A., Dumanović, J., Milovanović, Z., Jaćević, V., Chvojkova, M., Holubova, K., Vales, K., Skoupilova, V., Valko, M., Jomova, K., Alomar, S. Y., Botelho, F. D., Franca, T. C. C., Kuca, K., Hodny, Z.,& Nepovimova, E.. (2023). Frentizole derivatives with mTOR inhibiting and senomorphic properties. in Biomedicine & Pharmacotherapy
Elsevier., 167, 115600.
https://doi.org/10.1016/j.biopha.2023.115600

Chrienova Z, Rysanek D, Novak J, Vasicova P, Oleksak P, Andrys R, Skarka A, Dumanović J, Milovanović Z, Jaćević V, Chvojkova M, Holubova K, Vales K, Skoupilova V, Valko M, Jomova K, Alomar SY, Botelho FD, Franca TCC, Kuca K, Hodny Z, Nepovimova E. Frentizole derivatives with mTOR inhibiting and senomorphic properties. in Biomedicine & Pharmacotherapy. 2023;167:115600.
doi:10.1016/j.biopha.2023.115600 .

Chrienova, Zofia, Rysanek, David, Novak, Josef, Vasicova, Pavla, Oleksak, Patrik, Andrys, Rudolf, Skarka, Adam, Dumanović, Jelena, Milovanović, Zoran, Jaćević, Vesna, Chvojkova, Marketa, Holubova, Kristina, Vales, Karel, Skoupilova, Veronika, Valko, Marian, Jomova, Klaudia, Alomar, Suliman Y., Botelho, Fernanda D., Franca, Tanos C. C., Kuca, Kamil, Hodny, Zdenek, Nepovimova, Eugenie, "Frentizole derivatives with mTOR inhibiting and senomorphic properties" in Biomedicine & Pharmacotherapy, 167 (2023):115600,
https://doi.org/10.1016/j.biopha.2023.115600 . .

TY  - JOUR
AU  - Dumanović, Jelena
AU  - Nepovimova, Eugenie
AU  - Natić, Maja
AU  - Kuča, Kamil
AU  - Jaćević, Vesna
PY  - 2021
UR  - https://www.frontiersin.org/articles/10.3389/fpls.2020.552969/full
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/4452
AB  - In plants, there's a complex and multilevel network of the antioxidative system (AOS) operating to counteract harmful reactive species (RS), the foremost important of which are reactive oxygen species (ROS), and maintain homeostasis within the cell. Specific AOSs for plant cells are, first and foremost, enzymes of the glutathione-ascorbate cycle (Asc-GSH), followed by phenolic compounds and lipophilic antioxidants like carotenoids and tocopherols. Evidence that plant cells have excellent antioxidative defence systems is their ability to survive at H2O2 concentrations incompatible with animal cell life. For the survival of stressed plants, it's of particular importance that AOS cooperate and participate in redox reactions, therefore providing better protection and regeneration of the active reduced forms. Considering that plants abound in antioxidant compounds, and humans are not predisposed to synthesize the majority of them, new fields of research have emerged. Antioxidant potential of plant compounds has been exploited for antiaging formulations preparation, food fortification and preservation, but also in designing new therapies for diseases with oxidative stress implicated in aetiology.
PB  - Frontiers
T2  - Frontiers in Plant Science
T1  - The Significance of Reactive Oxygen Species and Antioxidant Defense System in Plants: A Concise Overview
VL  - 11
SP  - 552969
DO  - 10.3389/fpls.2020.552969
ER  - 

@article{
author = "Dumanović, Jelena and Nepovimova, Eugenie and Natić, Maja and Kuča, Kamil and Jaćević, Vesna",
year = "2021",
abstract = "In plants, there's a complex and multilevel network of the antioxidative system (AOS) operating to counteract harmful reactive species (RS), the foremost important of which are reactive oxygen species (ROS), and maintain homeostasis within the cell. Specific AOSs for plant cells are, first and foremost, enzymes of the glutathione-ascorbate cycle (Asc-GSH), followed by phenolic compounds and lipophilic antioxidants like carotenoids and tocopherols. Evidence that plant cells have excellent antioxidative defence systems is their ability to survive at H2O2 concentrations incompatible with animal cell life. For the survival of stressed plants, it's of particular importance that AOS cooperate and participate in redox reactions, therefore providing better protection and regeneration of the active reduced forms. Considering that plants abound in antioxidant compounds, and humans are not predisposed to synthesize the majority of them, new fields of research have emerged. Antioxidant potential of plant compounds has been exploited for antiaging formulations preparation, food fortification and preservation, but also in designing new therapies for diseases with oxidative stress implicated in aetiology.",
publisher = "Frontiers",
journal = "Frontiers in Plant Science",
title = "The Significance of Reactive Oxygen Species and Antioxidant Defense System in Plants: A Concise Overview",
volume = "11",
pages = "552969",
doi = "10.3389/fpls.2020.552969"
}

Dumanović, J., Nepovimova, E., Natić, M., Kuča, K.,& Jaćević, V.. (2021). The Significance of Reactive Oxygen Species and Antioxidant Defense System in Plants: A Concise Overview. in Frontiers in Plant Science
Frontiers., 11, 552969.
https://doi.org/10.3389/fpls.2020.552969

Dumanović J, Nepovimova E, Natić M, Kuča K, Jaćević V. The Significance of Reactive Oxygen Species and Antioxidant Defense System in Plants: A Concise Overview. in Frontiers in Plant Science. 2021;11:552969.
doi:10.3389/fpls.2020.552969 .

Dumanović, Jelena, Nepovimova, Eugenie, Natić, Maja, Kuča, Kamil, Jaćević, Vesna, "The Significance of Reactive Oxygen Species and Antioxidant Defense System in Plants: A Concise Overview" in Frontiers in Plant Science, 11 (2021):552969,
https://doi.org/10.3389/fpls.2020.552969 . .

TY  - JOUR
AU  - Jaćević, Vesna
AU  - Dumanović, Jelena
AU  - Lazarević, Miodrag
AU  - Nepovimova, Eugenie
AU  - Resanović, Radmila
AU  - Milovanović, Zoran
AU  - Wu, Qinghua
AU  - Kuča, Kamil
PY  - 2020
UR  - https://cherry.chem.bg.ac.rs/handle/123456789/4258
AB  - In this paper, the potential antidote efficacy of commercially available formulations of various feed additives such as Minazel-Plus®, Mycosorb®, and Mycofix® was considered by recording their incidence on general health, body weight, and food and water intake, as well as through histopathology and semiquantitative analysis of gastric alterations in Wistar rats treated with the T-2 toxin in a single-dose regimen of 1.67 mg/kg p.o. (1 LD50) for 4 weeks. As an organic adsorbent, Mycosorb® successfully antagonized acute lethal incidence of the T-2 toxin (protective index (PI) = 2.25; p < 0.05 vs. T-2 toxin), and had adverse effects on body weight gain as well as food and water intake during the research (p < 0.001). However, the protective efficacy of the other two food additives was significantly lower (p < 0.05). Treatment with Mycosorb® significantly reduced the severity of gastric damage, which was not the case when the other two adsorbents were used. Our results suggest that Mycosorb® is a much better adsorbent for preventing the adverse impact of the T-2 toxin as well as its toxic metabolites compared with Minazel-plus® or Mycofix-plus®, and it almost completely suppresses its acute toxic effects and cytotoxic potential on the gastric epithelial, glandular, and vascular endothelial cells.
PB  - MDPI
T2  - Toxins
T1  - Antidotal Potency of the Novel, Structurally Different Adsorbents in Rats Acutely Intoxicated with the T-2 Toxin
VL  - 12
IS  - 10
SP  - 643
DO  - 10.3390/toxins12100643
ER  - 

@article{
author = "Jaćević, Vesna and Dumanović, Jelena and Lazarević, Miodrag and Nepovimova, Eugenie and Resanović, Radmila and Milovanović, Zoran and Wu, Qinghua and Kuča, Kamil",
year = "2020",
abstract = "In this paper, the potential antidote efficacy of commercially available formulations of various feed additives such as Minazel-Plus®, Mycosorb®, and Mycofix® was considered by recording their incidence on general health, body weight, and food and water intake, as well as through histopathology and semiquantitative analysis of gastric alterations in Wistar rats treated with the T-2 toxin in a single-dose regimen of 1.67 mg/kg p.o. (1 LD50) for 4 weeks. As an organic adsorbent, Mycosorb® successfully antagonized acute lethal incidence of the T-2 toxin (protective index (PI) = 2.25; p < 0.05 vs. T-2 toxin), and had adverse effects on body weight gain as well as food and water intake during the research (p < 0.001). However, the protective efficacy of the other two food additives was significantly lower (p < 0.05). Treatment with Mycosorb® significantly reduced the severity of gastric damage, which was not the case when the other two adsorbents were used. Our results suggest that Mycosorb® is a much better adsorbent for preventing the adverse impact of the T-2 toxin as well as its toxic metabolites compared with Minazel-plus® or Mycofix-plus®, and it almost completely suppresses its acute toxic effects and cytotoxic potential on the gastric epithelial, glandular, and vascular endothelial cells.",
publisher = "MDPI",
journal = "Toxins",
title = "Antidotal Potency of the Novel, Structurally Different Adsorbents in Rats Acutely Intoxicated with the T-2 Toxin",
volume = "12",
number = "10",
pages = "643",
doi = "10.3390/toxins12100643"
}

Jaćević, V., Dumanović, J., Lazarević, M., Nepovimova, E., Resanović, R., Milovanović, Z., Wu, Q.,& Kuča, K.. (2020). Antidotal Potency of the Novel, Structurally Different Adsorbents in Rats Acutely Intoxicated with the T-2 Toxin. in Toxins
MDPI., 12(10), 643.
https://doi.org/10.3390/toxins12100643

Jaćević V, Dumanović J, Lazarević M, Nepovimova E, Resanović R, Milovanović Z, Wu Q, Kuča K. Antidotal Potency of the Novel, Structurally Different Adsorbents in Rats Acutely Intoxicated with the T-2 Toxin. in Toxins. 2020;12(10):643.
doi:10.3390/toxins12100643 .

Jaćević, Vesna, Dumanović, Jelena, Lazarević, Miodrag, Nepovimova, Eugenie, Resanović, Radmila, Milovanović, Zoran, Wu, Qinghua, Kuča, Kamil, "Antidotal Potency of the Novel, Structurally Different Adsorbents in Rats Acutely Intoxicated with the T-2 Toxin" in Toxins, 12, no. 10 (2020):643,
https://doi.org/10.3390/toxins12100643 . .