TY  - JOUR
AU  - Tabrizian, Kaveh
AU  - Miri, Fatemeh
AU  - Haseli, Shiva
AU  - Shahraki, Jafar
AU  - Belaran, Maryam
AU  - Rezaee, Ramin
AU  - Buha, Aleksandra
AU  - Tsatsakis, Aristidis
AU  - Arsene, Andreea Letiția
AU  - Șerban, Dragoș
AU  - Velescu, Bruno Ștefan
AU  - Hashemzaei, Mahmoud
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4315
AB  - There is controversy on the effect of statins on cognitive functions such as spatial memory. In the present study, effect of ten- day oral gavage of rosuvastatin (Ros, 20 mg/kg) on spatial learning and spatial memory retention impaired by H-89, was investigated in male rats. This study was comprised of two sets of experiments each including the following 3 groups (n = 8): Control group treated with DMSO; H-89 group received bilateral intra-hippocampal H-89 (10 μM/side, in DMSO) and Ros- H-89 group orally treated with Ros (20 mg/kg) and H-89 (similar to the H-89 group). For spatial learning (acquisition phase) assessment, from day 7 of Ros gavage, rats were trained in the Morris water maze (MWM) for four days (one block of 4 stages each day) and received daily H-89, 30 min after Ros gavage. On day 11, the probe test was performed. Also, to assess spatial memory retention, from day 7 to 10 of Ros gavage, rats were trained in MWM but received H-89 on day 10 only. On day 12, the probe test was performed. Besides, CREB and p-CREB protein expression was assessed in hippocampal samples and oxidative stress status was assessed in serum samples. We observed that H-89 led to a clear impairment of the spatial learning and spatial memory recall, increased levels of lipid peroxidation and downregulated CREB and p-CREB proteins, compared to the control group. However, Ros prevented H-89-induced deleterious consequences which might be probably in part due to its ameliorative effects on lipid peroxidation index and CREB and p-CREB expression.
PB  - Societatea de Științe Farmaceutice din România
T2  - Farmacia
T1  - Behavioural and molecular study of the effects of rosuvastatin on acquisition and retention of spatial memory impaired by H-89 in rats
VL  - 70
IS  - 5
SP  - 904
EP  - 911
DO  - 10.31925/farmacia.2022.5.16
ER  - 

@article{
author = "Tabrizian, Kaveh and Miri, Fatemeh and Haseli, Shiva and Shahraki, Jafar and Belaran, Maryam and Rezaee, Ramin and Buha, Aleksandra and Tsatsakis, Aristidis and Arsene, Andreea Letiția and Șerban, Dragoș and Velescu, Bruno Ștefan and Hashemzaei, Mahmoud",
year = "2022",
abstract = "There is controversy on the effect of statins on cognitive functions such as spatial memory. In the present study, effect of ten- day oral gavage of rosuvastatin (Ros, 20 mg/kg) on spatial learning and spatial memory retention impaired by H-89, was investigated in male rats. This study was comprised of two sets of experiments each including the following 3 groups (n = 8): Control group treated with DMSO; H-89 group received bilateral intra-hippocampal H-89 (10 μM/side, in DMSO) and Ros- H-89 group orally treated with Ros (20 mg/kg) and H-89 (similar to the H-89 group). For spatial learning (acquisition phase) assessment, from day 7 of Ros gavage, rats were trained in the Morris water maze (MWM) for four days (one block of 4 stages each day) and received daily H-89, 30 min after Ros gavage. On day 11, the probe test was performed. Also, to assess spatial memory retention, from day 7 to 10 of Ros gavage, rats were trained in MWM but received H-89 on day 10 only. On day 12, the probe test was performed. Besides, CREB and p-CREB protein expression was assessed in hippocampal samples and oxidative stress status was assessed in serum samples. We observed that H-89 led to a clear impairment of the spatial learning and spatial memory recall, increased levels of lipid peroxidation and downregulated CREB and p-CREB proteins, compared to the control group. However, Ros prevented H-89-induced deleterious consequences which might be probably in part due to its ameliorative effects on lipid peroxidation index and CREB and p-CREB expression.",
publisher = "Societatea de Științe Farmaceutice din România",
journal = "Farmacia",
title = "Behavioural and molecular study of the effects of rosuvastatin on acquisition and retention of spatial memory impaired by H-89 in rats",
volume = "70",
number = "5",
pages = "904-911",
doi = "10.31925/farmacia.2022.5.16"
}

Tabrizian, K., Miri, F., Haseli, S., Shahraki, J., Belaran, M., Rezaee, R., Buha, A., Tsatsakis, A., Arsene, A. L., Șerban, D., Velescu, B. Ș.,& Hashemzaei, M.. (2022). Behavioural and molecular study of the effects of rosuvastatin on acquisition and retention of spatial memory impaired by H-89 in rats. in Farmacia
Societatea de Științe Farmaceutice din România., 70(5), 904-911.
https://doi.org/10.31925/farmacia.2022.5.16

Tabrizian K, Miri F, Haseli S, Shahraki J, Belaran M, Rezaee R, Buha A, Tsatsakis A, Arsene AL, Șerban D, Velescu BȘ, Hashemzaei M. Behavioural and molecular study of the effects of rosuvastatin on acquisition and retention of spatial memory impaired by H-89 in rats. in Farmacia. 2022;70(5):904-911.
doi:10.31925/farmacia.2022.5.16 .

Tabrizian, Kaveh, Miri, Fatemeh, Haseli, Shiva, Shahraki, Jafar, Belaran, Maryam, Rezaee, Ramin, Buha, Aleksandra, Tsatsakis, Aristidis, Arsene, Andreea Letiția, Șerban, Dragoș, Velescu, Bruno Ștefan, Hashemzaei, Mahmoud, "Behavioural and molecular study of the effects of rosuvastatin on acquisition and retention of spatial memory impaired by H-89 in rats" in Farmacia, 70, no. 5 (2022):904-911,
https://doi.org/10.31925/farmacia.2022.5.16 . .

TY  - JOUR
AU  - Wallace, David R.
AU  - Taalab, Yasmeen M.
AU  - Heinze, Sarah
AU  - Tariba Lovaković, Sarah
AU  - Pizent, Alica
AU  - Renieri, Elisavit
AU  - Tsatsakis, Aristidis
AU  - Farooqi, Ammad Ahmad
AU  - Javorac, Dragana
AU  - Anđelković, Milena
AU  - Bulat, Zorica
AU  - Antonijević, Biljana
AU  - Buha-Đorđević, Aleksandra
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3578
AB  - Toxic metals are extensively found in the environment, households, and workplaces and contaminate food and drinking water. The crosstalk between environmental exposure to toxic metals and human diseases has been frequently described. The toxic mechanism of action was classically viewed as the ability to dysregulate the redox status, production of inflammatory mediators and alteration of mitochondrial function. Recently, growing evidence showed that heavy metals might exert their toxicity through microRNAs (miRNA)-short, single-stranded, noncoding molecules that function as positive/negative regulators of gene expression. Aberrant alteration of the endogenous miRNA has been directly implicated in various pathophysiological conditions and signaling pathways, consequently leading to different types of cancer and human diseases. Additionally, the gene-regulatory capacity of miRNAs is particularly valuable in the brain-a complex organ with neurons demonstrating a significant ability to adapt following environmental stimuli. Accordingly, dysregulated miRNAs identified in patients suffering from neurological diseases might serve as biomarkers for the earlier diagnosis and monitoring of disease progression. This review will greatly emphasize the effect of the toxic metals on human miRNA activities and how this contributes to progression of diseases such as cancer and neurodegenerative disorders (NDDs).
PB  - MDPI
T2  - Cells
T1  - Toxic-Metal-Induced Alteration in miRNA Expression Profile as a Proposed Mechanism for Disease Development
VL  - 9
IS  - 4
DO  - 10.3390/cells9040901
ER  - 

@article{
author = "Wallace, David R. and Taalab, Yasmeen M. and Heinze, Sarah and Tariba Lovaković, Sarah and Pizent, Alica and Renieri, Elisavit and Tsatsakis, Aristidis and Farooqi, Ammad Ahmad and Javorac, Dragana and Anđelković, Milena and Bulat, Zorica and Antonijević, Biljana and Buha-Đorđević, Aleksandra",
year = "2020",
abstract = "Toxic metals are extensively found in the environment, households, and workplaces and contaminate food and drinking water. The crosstalk between environmental exposure to toxic metals and human diseases has been frequently described. The toxic mechanism of action was classically viewed as the ability to dysregulate the redox status, production of inflammatory mediators and alteration of mitochondrial function. Recently, growing evidence showed that heavy metals might exert their toxicity through microRNAs (miRNA)-short, single-stranded, noncoding molecules that function as positive/negative regulators of gene expression. Aberrant alteration of the endogenous miRNA has been directly implicated in various pathophysiological conditions and signaling pathways, consequently leading to different types of cancer and human diseases. Additionally, the gene-regulatory capacity of miRNAs is particularly valuable in the brain-a complex organ with neurons demonstrating a significant ability to adapt following environmental stimuli. Accordingly, dysregulated miRNAs identified in patients suffering from neurological diseases might serve as biomarkers for the earlier diagnosis and monitoring of disease progression. This review will greatly emphasize the effect of the toxic metals on human miRNA activities and how this contributes to progression of diseases such as cancer and neurodegenerative disorders (NDDs).",
publisher = "MDPI",
journal = "Cells",
title = "Toxic-Metal-Induced Alteration in miRNA Expression Profile as a Proposed Mechanism for Disease Development",
volume = "9",
number = "4",
doi = "10.3390/cells9040901"
}

Wallace, D. R., Taalab, Y. M., Heinze, S., Tariba Lovaković, S., Pizent, A., Renieri, E., Tsatsakis, A., Farooqi, A. A., Javorac, D., Anđelković, M., Bulat, Z., Antonijević, B.,& Buha-Đorđević, A.. (2020). Toxic-Metal-Induced Alteration in miRNA Expression Profile as a Proposed Mechanism for Disease Development. in Cells
MDPI., 9(4).
https://doi.org/10.3390/cells9040901

Wallace DR, Taalab YM, Heinze S, Tariba Lovaković S, Pizent A, Renieri E, Tsatsakis A, Farooqi AA, Javorac D, Anđelković M, Bulat Z, Antonijević B, Buha-Đorđević A. Toxic-Metal-Induced Alteration in miRNA Expression Profile as a Proposed Mechanism for Disease Development. in Cells. 2020;9(4).
doi:10.3390/cells9040901 .

Wallace, David R., Taalab, Yasmeen M., Heinze, Sarah, Tariba Lovaković, Sarah, Pizent, Alica, Renieri, Elisavit, Tsatsakis, Aristidis, Farooqi, Ammad Ahmad, Javorac, Dragana, Anđelković, Milena, Bulat, Zorica, Antonijević, Biljana, Buha-Đorđević, Aleksandra, "Toxic-Metal-Induced Alteration in miRNA Expression Profile as a Proposed Mechanism for Disease Development" in Cells, 9, no. 4 (2020),
https://doi.org/10.3390/cells9040901 . .

TY  - JOUR
AU  - Varmazyari, Atefeh
AU  - Taghizadehghalehjoughi, Ali
AU  - Sevim, Cigdem
AU  - Baris, Ozlem
AU  - Eser, Gizem
AU  - Yildirim, Serkan
AU  - Hacimuftuoglu, Ahmet
AU  - Buha, Aleksandra
AU  - Wallace, David R.
AU  - Tsatsakis, Aristidis
AU  - Aschner, Michael
AU  - Mezhuev, Yaroslav
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3593
AB  - Living organisms have an innate ability to regulate the synthesis of inorganic materials, such as bones and teeth in humans. Cadmium sulfide (CdS) can be utilized as a quantum dot that functions as a unique light-emitting semiconductor nanocrystal. The increased use in CdS has led to an increased inhalation and ingestion rate of CdS by humans which requires a broader appreciation for the acute and chronic toxicity of CdS. We investigated the toxic effects of CdS on cerebellar cell cultures and rat brain. We employed a ‘green synthesis’ biosynthesis process to obtain biocompatible material that can be used in living organisms, such as Viridibacillus arenosi K64. Nanocrystal formation was initiated by adding CdCl2 (1 mM) to the cell cultures. Our in vitro results established that increased concentrations of CdS (0.1 μg/mL) lead to decreased cell viability as assessed using 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT), total antioxidant capacity (TAC), and total oxidant status (TOS). The in vivo studies showed that exposure to CdS (1 mg/kg) glial fibrillary acidic protein (GFAP) and 8-hydroxy-2' -deoxyguanosine (8-OHdG) were increased. Collectively, we describe a model system that addresses the process from the synthesis to the neurotoxicity assessment for CdS both in vitro and in vivo. These data will be beneficial in establishing a more comprehensive pathway for the understanding of quantum dot-induced neurotoxicity.
PB  - Elsevier
T2  - Toxicology Reports
T1  - Cadmium sulfide-induced toxicity in the cortex and cerebellum: In vitro and in vivo studies
VL  - 7
SP  - 637
EP  - 648
DO  - 10.1016/j.toxrep.2020.04.011
ER  - 

@article{
author = "Varmazyari, Atefeh and Taghizadehghalehjoughi, Ali and Sevim, Cigdem and Baris, Ozlem and Eser, Gizem and Yildirim, Serkan and Hacimuftuoglu, Ahmet and Buha, Aleksandra and Wallace, David R. and Tsatsakis, Aristidis and Aschner, Michael and Mezhuev, Yaroslav",
year = "2020",
abstract = "Living organisms have an innate ability to regulate the synthesis of inorganic materials, such as bones and teeth in humans. Cadmium sulfide (CdS) can be utilized as a quantum dot that functions as a unique light-emitting semiconductor nanocrystal. The increased use in CdS has led to an increased inhalation and ingestion rate of CdS by humans which requires a broader appreciation for the acute and chronic toxicity of CdS. We investigated the toxic effects of CdS on cerebellar cell cultures and rat brain. We employed a ‘green synthesis’ biosynthesis process to obtain biocompatible material that can be used in living organisms, such as Viridibacillus arenosi K64. Nanocrystal formation was initiated by adding CdCl2 (1 mM) to the cell cultures. Our in vitro results established that increased concentrations of CdS (0.1 μg/mL) lead to decreased cell viability as assessed using 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT), total antioxidant capacity (TAC), and total oxidant status (TOS). The in vivo studies showed that exposure to CdS (1 mg/kg) glial fibrillary acidic protein (GFAP) and 8-hydroxy-2' -deoxyguanosine (8-OHdG) were increased. Collectively, we describe a model system that addresses the process from the synthesis to the neurotoxicity assessment for CdS both in vitro and in vivo. These data will be beneficial in establishing a more comprehensive pathway for the understanding of quantum dot-induced neurotoxicity.",
publisher = "Elsevier",
journal = "Toxicology Reports",
title = "Cadmium sulfide-induced toxicity in the cortex and cerebellum: In vitro and in vivo studies",
volume = "7",
pages = "637-648",
doi = "10.1016/j.toxrep.2020.04.011"
}

Varmazyari, A., Taghizadehghalehjoughi, A., Sevim, C., Baris, O., Eser, G., Yildirim, S., Hacimuftuoglu, A., Buha, A., Wallace, D. R., Tsatsakis, A., Aschner, M.,& Mezhuev, Y.. (2020). Cadmium sulfide-induced toxicity in the cortex and cerebellum: In vitro and in vivo studies. in Toxicology Reports
Elsevier., 7, 637-648.
https://doi.org/10.1016/j.toxrep.2020.04.011

Varmazyari A, Taghizadehghalehjoughi A, Sevim C, Baris O, Eser G, Yildirim S, Hacimuftuoglu A, Buha A, Wallace DR, Tsatsakis A, Aschner M, Mezhuev Y. Cadmium sulfide-induced toxicity in the cortex and cerebellum: In vitro and in vivo studies. in Toxicology Reports. 2020;7:637-648.
doi:10.1016/j.toxrep.2020.04.011 .

Varmazyari, Atefeh, Taghizadehghalehjoughi, Ali, Sevim, Cigdem, Baris, Ozlem, Eser, Gizem, Yildirim, Serkan, Hacimuftuoglu, Ahmet, Buha, Aleksandra, Wallace, David R., Tsatsakis, Aristidis, Aschner, Michael, Mezhuev, Yaroslav, "Cadmium sulfide-induced toxicity in the cortex and cerebellum: In vitro and in vivo studies" in Toxicology Reports, 7 (2020):637-648,
https://doi.org/10.1016/j.toxrep.2020.04.011 . .

TY  - JOUR
AU  - Panieri, Emiliano
AU  - Buha, Aleksandra
AU  - Telkoparan-Akillilar, Pelin
AU  - Cevik, Dilek
AU  - Kouretas, Demetrios
AU  - Veskoukis, Aristidis
AU  - Skaperda, Zoi
AU  - Tsatsakis, Aristidis
AU  - Wallace, David
AU  - Suzen, Sibel
AU  - Saso, Luciano
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3551
AB  - The nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.
PB  - MDPI
T2  - Antioxidants
T1  - Potential applications of NRF2 modulators in cancer therapy
VL  - 9
IS  - 3
DO  - 10.3390/antiox9030193
ER  - 

@article{
author = "Panieri, Emiliano and Buha, Aleksandra and Telkoparan-Akillilar, Pelin and Cevik, Dilek and Kouretas, Demetrios and Veskoukis, Aristidis and Skaperda, Zoi and Tsatsakis, Aristidis and Wallace, David and Suzen, Sibel and Saso, Luciano",
year = "2020",
abstract = "The nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.",
publisher = "MDPI",
journal = "Antioxidants",
title = "Potential applications of NRF2 modulators in cancer therapy",
volume = "9",
number = "3",
doi = "10.3390/antiox9030193"
}

Panieri, E., Buha, A., Telkoparan-Akillilar, P., Cevik, D., Kouretas, D., Veskoukis, A., Skaperda, Z., Tsatsakis, A., Wallace, D., Suzen, S.,& Saso, L.. (2020). Potential applications of NRF2 modulators in cancer therapy. in Antioxidants
MDPI., 9(3).
https://doi.org/10.3390/antiox9030193

Panieri E, Buha A, Telkoparan-Akillilar P, Cevik D, Kouretas D, Veskoukis A, Skaperda Z, Tsatsakis A, Wallace D, Suzen S, Saso L. Potential applications of NRF2 modulators in cancer therapy. in Antioxidants. 2020;9(3).
doi:10.3390/antiox9030193 .

Panieri, Emiliano, Buha, Aleksandra, Telkoparan-Akillilar, Pelin, Cevik, Dilek, Kouretas, Demetrios, Veskoukis, Aristidis, Skaperda, Zoi, Tsatsakis, Aristidis, Wallace, David, Suzen, Sibel, Saso, Luciano, "Potential applications of NRF2 modulators in cancer therapy" in Antioxidants, 9, no. 3 (2020),
https://doi.org/10.3390/antiox9030193 . .

TY  - JOUR
AU  - Hernandez, Antonio F.
AU  - Buha, Aleksandra
AU  - Constantin, Carolina
AU  - Wallace, David R.
AU  - Sarigiannis, Dimosthenis
AU  - Neagu, Monica
AU  - Antonijević, Biljana
AU  - Hayes, Wallace A.
AU  - Wilks, Martin F.
AU  - Tsatsakis, Aristidis
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3464
AB  - Humans are exposed to multiple chemicals on a daily basis instead of to just a single chemical, yet the majority of existing toxicity data comes from single-chemical exposure. Multiple factors must be considered such as the route, concentration, duration, and the timing of exposure when determining toxicity to the organism. The need for adequate model systems (in vivo, in vitro, in silico and mathematical) is paramount for better understanding of chemical mixture toxicity. Currently, shortcomings plague each model system as investigators struggle to find the appropriate balance of rigor, reproducibility and appropriateness in mixture toxicity studies. Significant questions exist when comparing single-to mixture-chemical toxicity concerning additivity, synergism, potentiation, or antagonism. Dose/concentration relevance is a major consideration and should be subthreshold for better accuracy in toxicity assessment. Previous work was limited by the technology and methodology of the time, but recent advances have resulted in significant progress in the study of mixture toxicology. Novel technologies have added insight to data obtained from in vivo studies for predictive toxicity testing. These include new in vitro models: omics-related tools, organs-on-a-chip and 3D cell culture, and in silico methods. Taken together, all these modern methodologies improve the understanding of the multiple toxicity pathways associated with adverse outcomes (e.g., adverse outcome pathways), thus allowing investigators to better predict risks linked to exposure to chemical mixtures. As technology and knowledge advance, our ability to harness and integrate separate streams of evidence regarding outcomes associated with chemical mixture exposure improves. As many national and international organizations are currently stressing, studies on chemical mixture toxicity are of primary importance.
PB  - Springer Verlag
T2  - Archives of Toxicology
T1  - Critical assessment and integration of separate lines of evidence for risk assessment of chemical mixtures
VL  - 93
IS  - 10
SP  - 2741
EP  - 2757
DO  - 10.1007/s00204-019-02547-x
ER  - 

@article{
author = "Hernandez, Antonio F. and Buha, Aleksandra and Constantin, Carolina and Wallace, David R. and Sarigiannis, Dimosthenis and Neagu, Monica and Antonijević, Biljana and Hayes, Wallace A. and Wilks, Martin F. and Tsatsakis, Aristidis",
year = "2019",
abstract = "Humans are exposed to multiple chemicals on a daily basis instead of to just a single chemical, yet the majority of existing toxicity data comes from single-chemical exposure. Multiple factors must be considered such as the route, concentration, duration, and the timing of exposure when determining toxicity to the organism. The need for adequate model systems (in vivo, in vitro, in silico and mathematical) is paramount for better understanding of chemical mixture toxicity. Currently, shortcomings plague each model system as investigators struggle to find the appropriate balance of rigor, reproducibility and appropriateness in mixture toxicity studies. Significant questions exist when comparing single-to mixture-chemical toxicity concerning additivity, synergism, potentiation, or antagonism. Dose/concentration relevance is a major consideration and should be subthreshold for better accuracy in toxicity assessment. Previous work was limited by the technology and methodology of the time, but recent advances have resulted in significant progress in the study of mixture toxicology. Novel technologies have added insight to data obtained from in vivo studies for predictive toxicity testing. These include new in vitro models: omics-related tools, organs-on-a-chip and 3D cell culture, and in silico methods. Taken together, all these modern methodologies improve the understanding of the multiple toxicity pathways associated with adverse outcomes (e.g., adverse outcome pathways), thus allowing investigators to better predict risks linked to exposure to chemical mixtures. As technology and knowledge advance, our ability to harness and integrate separate streams of evidence regarding outcomes associated with chemical mixture exposure improves. As many national and international organizations are currently stressing, studies on chemical mixture toxicity are of primary importance.",
publisher = "Springer Verlag",
journal = "Archives of Toxicology",
title = "Critical assessment and integration of separate lines of evidence for risk assessment of chemical mixtures",
volume = "93",
number = "10",
pages = "2741-2757",
doi = "10.1007/s00204-019-02547-x"
}

Hernandez, A. F., Buha, A., Constantin, C., Wallace, D. R., Sarigiannis, D., Neagu, M., Antonijević, B., Hayes, W. A., Wilks, M. F.,& Tsatsakis, A.. (2019). Critical assessment and integration of separate lines of evidence for risk assessment of chemical mixtures. in Archives of Toxicology
Springer Verlag., 93(10), 2741-2757.
https://doi.org/10.1007/s00204-019-02547-x

Hernandez AF, Buha A, Constantin C, Wallace DR, Sarigiannis D, Neagu M, Antonijević B, Hayes WA, Wilks MF, Tsatsakis A. Critical assessment and integration of separate lines of evidence for risk assessment of chemical mixtures. in Archives of Toxicology. 2019;93(10):2741-2757.
doi:10.1007/s00204-019-02547-x .

Hernandez, Antonio F., Buha, Aleksandra, Constantin, Carolina, Wallace, David R., Sarigiannis, Dimosthenis, Neagu, Monica, Antonijević, Biljana, Hayes, Wallace A., Wilks, Martin F., Tsatsakis, Aristidis, "Critical assessment and integration of separate lines of evidence for risk assessment of chemical mixtures" in Archives of Toxicology, 93, no. 10 (2019):2741-2757,
https://doi.org/10.1007/s00204-019-02547-x . .