TY  - JOUR
AU  - Čupić, Željko
AU  - Stanojevic, Ana
AU  - Marković, Vladimir M.
AU  - Kolar-Anić, Ljiljana
AU  - Terenius, Lars
AU  - Vukojevic, Vladana
PY  - 2017
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/2087
AB  - Stress and alcohol use are interrelatedstress contributes to the initiation and upholding of alcohol use and alcohol use alters the way we perceive and respond to stress. Intricate mechanisms through which ethanol alters the organism's response to stress remain elusive. We have developed a stoichiometric network model to succinctly describe neurochemical transformations underlying the stress response axis and use numerical simulations to model ethanol effects on complex daily changes of blood levels of cholesterol, 6 peptide and 8 steroid hormones. Modelling suggests that ethanol alters the dynamical regulation of hypothalamic-pituitary-adrenal (HPA) axis activity by affecting the amplitude of ultradian oscillations of HPA axis hormones, which defines the threshold with respect to which the response to stress is being set. These effects are complexlow/moderate acute ethanol challenge ( LT  8mM) may reduce, leave unaltered or increase the amplitude of ultradian cortisol (CORT) oscillations, giving rise to an intricate response at the organism level, offering also a potential explanation as to why apparently discordant results were observed in experimental studies. In contrast, high-dose acute ethanol challenge (> 8mM) increases instantaneous CORT levels and the amplitude of ultradian CORT oscillations in a dose-dependent manner, affecting the HPA axis activity also during the following day(s). Chronic exposure to ethanol qualitatively changes the HPA axis dynamics, whereas ethanol at intoxicating levels shuts down this dynamic regulation mechanism. Mathematical modelling gives a quantitative biology-based framework that can be used for predicting how the integral HPA axis response is perturbed by alcohol.
PB  - Wiley, Hoboken
T2  - Addiction Biology
T1  - The HPA axis and ethanol: a synthesis of mathematical modelling and experimental observations
VL  - 22
IS  - 6
SP  - 1486
EP  - 1500
DO  - 10.1111/adb.12409
ER  - 

@article{
author = "Čupić, Željko and Stanojevic, Ana and Marković, Vladimir M. and Kolar-Anić, Ljiljana and Terenius, Lars and Vukojevic, Vladana",
year = "2017",
abstract = "Stress and alcohol use are interrelatedstress contributes to the initiation and upholding of alcohol use and alcohol use alters the way we perceive and respond to stress. Intricate mechanisms through which ethanol alters the organism's response to stress remain elusive. We have developed a stoichiometric network model to succinctly describe neurochemical transformations underlying the stress response axis and use numerical simulations to model ethanol effects on complex daily changes of blood levels of cholesterol, 6 peptide and 8 steroid hormones. Modelling suggests that ethanol alters the dynamical regulation of hypothalamic-pituitary-adrenal (HPA) axis activity by affecting the amplitude of ultradian oscillations of HPA axis hormones, which defines the threshold with respect to which the response to stress is being set. These effects are complexlow/moderate acute ethanol challenge ( LT  8mM) may reduce, leave unaltered or increase the amplitude of ultradian cortisol (CORT) oscillations, giving rise to an intricate response at the organism level, offering also a potential explanation as to why apparently discordant results were observed in experimental studies. In contrast, high-dose acute ethanol challenge (> 8mM) increases instantaneous CORT levels and the amplitude of ultradian CORT oscillations in a dose-dependent manner, affecting the HPA axis activity also during the following day(s). Chronic exposure to ethanol qualitatively changes the HPA axis dynamics, whereas ethanol at intoxicating levels shuts down this dynamic regulation mechanism. Mathematical modelling gives a quantitative biology-based framework that can be used for predicting how the integral HPA axis response is perturbed by alcohol.",
publisher = "Wiley, Hoboken",
journal = "Addiction Biology",
title = "The HPA axis and ethanol: a synthesis of mathematical modelling and experimental observations",
volume = "22",
number = "6",
pages = "1486-1500",
doi = "10.1111/adb.12409"
}

Čupić, Ž., Stanojevic, A., Marković, V. M., Kolar-Anić, L., Terenius, L.,& Vukojevic, V.. (2017). The HPA axis and ethanol: a synthesis of mathematical modelling and experimental observations. in Addiction Biology
Wiley, Hoboken., 22(6), 1486-1500.
https://doi.org/10.1111/adb.12409

Čupić Ž, Stanojevic A, Marković VM, Kolar-Anić L, Terenius L, Vukojevic V. The HPA axis and ethanol: a synthesis of mathematical modelling and experimental observations. in Addiction Biology. 2017;22(6):1486-1500.
doi:10.1111/adb.12409 .

Čupić, Željko, Stanojevic, Ana, Marković, Vladimir M., Kolar-Anić, Ljiljana, Terenius, Lars, Vukojevic, Vladana, "The HPA axis and ethanol: a synthesis of mathematical modelling and experimental observations" in Addiction Biology, 22, no. 6 (2017):1486-1500,
https://doi.org/10.1111/adb.12409 . .

TY  - JOUR
AU  - Abulseoud, Osama A.
AU  - Ho, Man Choi
AU  - Choi, Doo-Sup
AU  - Stanojevic, Ana
AU  - Čupić, Željko
AU  - Kolar-Anić, Ljiljana
AU  - Vukojevic, Vladana
PY  - 2017
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/2269
AB  - Changes in the hypothalamic-pituitary-adrenal (HPA) axis activity constitute a key component of bipolar mania, but the extent and nature of these alterations are not fully understood. We use here the lateral hypothalamic-kindled (LHK) rat model to deliberately induce an acute manic-like episode and measure serum corticosterone concentrations to assess changes in HPA axis activity. A mathematical model is developed to succinctly describe the entwined biochemical transformations that underlay the HPA axis and emulate by numerical simulations the considerable increase in serum corticosterone concentration induced by LHK. Synergistic combination of the LHK rat model and dynamical systems theory allows us to quantitatively characterize changes in HPA axis activity under controlled induction of acute manic-like states and provides a framework to study in silico how the dynamic integration of neurochemical transformations underlying the HPA axis is disrupted in these states.
PB  - Public Library of Science (PLoS)
T2  - Plos One
T1  - Corticosterone oscillations during mania induction in the lateral hypothalamic kindled rat-Experimental observations and mathematical modeling
VL  - 12
IS  - 5
DO  - 10.1371/journal.pone.0177551
ER  - 

@article{
author = "Abulseoud, Osama A. and Ho, Man Choi and Choi, Doo-Sup and Stanojevic, Ana and Čupić, Željko and Kolar-Anić, Ljiljana and Vukojevic, Vladana",
year = "2017",
abstract = "Changes in the hypothalamic-pituitary-adrenal (HPA) axis activity constitute a key component of bipolar mania, but the extent and nature of these alterations are not fully understood. We use here the lateral hypothalamic-kindled (LHK) rat model to deliberately induce an acute manic-like episode and measure serum corticosterone concentrations to assess changes in HPA axis activity. A mathematical model is developed to succinctly describe the entwined biochemical transformations that underlay the HPA axis and emulate by numerical simulations the considerable increase in serum corticosterone concentration induced by LHK. Synergistic combination of the LHK rat model and dynamical systems theory allows us to quantitatively characterize changes in HPA axis activity under controlled induction of acute manic-like states and provides a framework to study in silico how the dynamic integration of neurochemical transformations underlying the HPA axis is disrupted in these states.",
publisher = "Public Library of Science (PLoS)",
journal = "Plos One",
title = "Corticosterone oscillations during mania induction in the lateral hypothalamic kindled rat-Experimental observations and mathematical modeling",
volume = "12",
number = "5",
doi = "10.1371/journal.pone.0177551"
}

Abulseoud, O. A., Ho, M. C., Choi, D., Stanojevic, A., Čupić, Ž., Kolar-Anić, L.,& Vukojevic, V.. (2017). Corticosterone oscillations during mania induction in the lateral hypothalamic kindled rat-Experimental observations and mathematical modeling. in Plos One
Public Library of Science (PLoS)., 12(5).
https://doi.org/10.1371/journal.pone.0177551

Abulseoud OA, Ho MC, Choi D, Stanojevic A, Čupić Ž, Kolar-Anić L, Vukojevic V. Corticosterone oscillations during mania induction in the lateral hypothalamic kindled rat-Experimental observations and mathematical modeling. in Plos One. 2017;12(5).
doi:10.1371/journal.pone.0177551 .

Abulseoud, Osama A., Ho, Man Choi, Choi, Doo-Sup, Stanojevic, Ana, Čupić, Željko, Kolar-Anić, Ljiljana, Vukojevic, Vladana, "Corticosterone oscillations during mania induction in the lateral hypothalamic kindled rat-Experimental observations and mathematical modeling" in Plos One, 12, no. 5 (2017),
https://doi.org/10.1371/journal.pone.0177551 . .

TY  - JOUR
AU  - Marković, Vladimir M.
AU  - Čupić, Željko
AU  - Macesic, Stevan
AU  - Stanojevic, Ana
AU  - Vukojevic, Vladana
AU  - Kolar-Anić, Ljiljana
PY  - 2016
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/1929
AB  - A mathematical model of the hypothalamic-pituitary-adrenal (HPA) axis with cholesterol as a dynamical variable was derived to investigate the effects of cholesterol, the primary precursor of all steroid hormones, on the ultradian and circadian HPA axis activity. To develop the model, the parameter space was systematically examined by stoichiometric network analysis to identify conditions for ultradian oscillations, determine conditions under which dynamic transitions, i.e. bifurcations occur and identify bifurcation types. The bifurcations were further characterized using numerical simulations. Model predictions agree well with empirical findings reported in the literature, indicating that cholesterol levels may critically affect the global dynamics of the HPA axis. The proposed model provides a base for better understanding of experimental observations, it may be used as a tool for designing experiments and offers useful insights into the characteristics of basic dynamic regulatory mechanisms that, when impaired, may lead to the development of some modern-lifestyle-associated diseases.
PB  - Oxford Univ Press, Oxford
T2  - Mathematical Medicine and Biology-A Journal of the Ima
T1  - Modelling cholesterol effects on the dynamics of the hypothalamic-pituitary-adrenal (HPA) axis
VL  - 33
IS  - 1
SP  - 1
EP  - 28
DO  - 10.1093/imammb/dqu020
ER  - 

@article{
author = "Marković, Vladimir M. and Čupić, Željko and Macesic, Stevan and Stanojevic, Ana and Vukojevic, Vladana and Kolar-Anić, Ljiljana",
year = "2016",
abstract = "A mathematical model of the hypothalamic-pituitary-adrenal (HPA) axis with cholesterol as a dynamical variable was derived to investigate the effects of cholesterol, the primary precursor of all steroid hormones, on the ultradian and circadian HPA axis activity. To develop the model, the parameter space was systematically examined by stoichiometric network analysis to identify conditions for ultradian oscillations, determine conditions under which dynamic transitions, i.e. bifurcations occur and identify bifurcation types. The bifurcations were further characterized using numerical simulations. Model predictions agree well with empirical findings reported in the literature, indicating that cholesterol levels may critically affect the global dynamics of the HPA axis. The proposed model provides a base for better understanding of experimental observations, it may be used as a tool for designing experiments and offers useful insights into the characteristics of basic dynamic regulatory mechanisms that, when impaired, may lead to the development of some modern-lifestyle-associated diseases.",
publisher = "Oxford Univ Press, Oxford",
journal = "Mathematical Medicine and Biology-A Journal of the Ima",
title = "Modelling cholesterol effects on the dynamics of the hypothalamic-pituitary-adrenal (HPA) axis",
volume = "33",
number = "1",
pages = "1-28",
doi = "10.1093/imammb/dqu020"
}

Marković, V. M., Čupić, Ž., Macesic, S., Stanojevic, A., Vukojevic, V.,& Kolar-Anić, L.. (2016). Modelling cholesterol effects on the dynamics of the hypothalamic-pituitary-adrenal (HPA) axis. in Mathematical Medicine and Biology-A Journal of the Ima
Oxford Univ Press, Oxford., 33(1), 1-28.
https://doi.org/10.1093/imammb/dqu020

Marković VM, Čupić Ž, Macesic S, Stanojevic A, Vukojevic V, Kolar-Anić L. Modelling cholesterol effects on the dynamics of the hypothalamic-pituitary-adrenal (HPA) axis. in Mathematical Medicine and Biology-A Journal of the Ima. 2016;33(1):1-28.
doi:10.1093/imammb/dqu020 .

Marković, Vladimir M., Čupić, Željko, Macesic, Stevan, Stanojevic, Ana, Vukojevic, Vladana, Kolar-Anić, Ljiljana, "Modelling cholesterol effects on the dynamics of the hypothalamic-pituitary-adrenal (HPA) axis" in Mathematical Medicine and Biology-A Journal of the Ima, 33, no. 1 (2016):1-28,
https://doi.org/10.1093/imammb/dqu020 . .

TY  - JOUR
AU  - Čupić, Željko
AU  - Marković, Vladimir M.
AU  - Macesic, Stevan
AU  - Stanojevic, Ana
AU  - Damjanovic, Svetozar
AU  - Vukojevic, Vladana
AU  - Kolar-Anić, Ljiljana
PY  - 2016
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/2036
AB  - Dynamic properties of a nonlinear five-dimensional stoichiometric model of the hypothalamicpituitary-adrenal (HPA) axis were systematically investigated. Conditions under which qualitative transitions between dynamic states occur are determined by independently varying the rate constants of all reactions that constitute the model. Bifurcation types were further characterized using continuation algorithms and scale factor methods. Regions of bistability and transitions through supercritical Andronov-Hopf and saddle loop bifurcations were identified. Dynamic state analysis predicts that the HPA axis operates under basal (healthy) physiological conditions close to an Andronov-Hopf bifurcation. Dynamic properties of the stress-control axis have not been characterized experimentally, but modelling suggests that the proximity to a supercritical Andronov-Hopf bifurcation can give the HPA axis both, flexibility to respond to external stimuli and adjust to new conditions and stability, i.e., the capacity to return to the original dynamic state afterwards, which is essential for maintaining homeostasis. The analysis presented here reflects the properties of a low-dimensional model that succinctly describes neurochemical transformations underlying the HPA axis. However, the model accounts correctly for a number of experimentally observed properties of the stress-response axis. We therefore regard that the presented analysis is meaningful, showing how in silico investigations can be used to guide the experimentalists in understanding how the HPA axis activity changes under chronic disease and/or specific pharmacological manipulations.
PB  - Amer Inst Physics, Melville
T2  - Chaos
T1  - Dynamic transitions in a model of the hypothalamic-pituitary-adrenal axis
VL  - 26
IS  - 3
DO  - 10.1063/1.4944040
ER  - 

@article{
author = "Čupić, Željko and Marković, Vladimir M. and Macesic, Stevan and Stanojevic, Ana and Damjanovic, Svetozar and Vukojevic, Vladana and Kolar-Anić, Ljiljana",
year = "2016",
abstract = "Dynamic properties of a nonlinear five-dimensional stoichiometric model of the hypothalamicpituitary-adrenal (HPA) axis were systematically investigated. Conditions under which qualitative transitions between dynamic states occur are determined by independently varying the rate constants of all reactions that constitute the model. Bifurcation types were further characterized using continuation algorithms and scale factor methods. Regions of bistability and transitions through supercritical Andronov-Hopf and saddle loop bifurcations were identified. Dynamic state analysis predicts that the HPA axis operates under basal (healthy) physiological conditions close to an Andronov-Hopf bifurcation. Dynamic properties of the stress-control axis have not been characterized experimentally, but modelling suggests that the proximity to a supercritical Andronov-Hopf bifurcation can give the HPA axis both, flexibility to respond to external stimuli and adjust to new conditions and stability, i.e., the capacity to return to the original dynamic state afterwards, which is essential for maintaining homeostasis. The analysis presented here reflects the properties of a low-dimensional model that succinctly describes neurochemical transformations underlying the HPA axis. However, the model accounts correctly for a number of experimentally observed properties of the stress-response axis. We therefore regard that the presented analysis is meaningful, showing how in silico investigations can be used to guide the experimentalists in understanding how the HPA axis activity changes under chronic disease and/or specific pharmacological manipulations.",
publisher = "Amer Inst Physics, Melville",
journal = "Chaos",
title = "Dynamic transitions in a model of the hypothalamic-pituitary-adrenal axis",
volume = "26",
number = "3",
doi = "10.1063/1.4944040"
}

Čupić, Ž., Marković, V. M., Macesic, S., Stanojevic, A., Damjanovic, S., Vukojevic, V.,& Kolar-Anić, L.. (2016). Dynamic transitions in a model of the hypothalamic-pituitary-adrenal axis. in Chaos
Amer Inst Physics, Melville., 26(3).
https://doi.org/10.1063/1.4944040

Čupić Ž, Marković VM, Macesic S, Stanojevic A, Damjanovic S, Vukojevic V, Kolar-Anić L. Dynamic transitions in a model of the hypothalamic-pituitary-adrenal axis. in Chaos. 2016;26(3).
doi:10.1063/1.4944040 .

Čupić, Željko, Marković, Vladimir M., Macesic, Stevan, Stanojevic, Ana, Damjanovic, Svetozar, Vukojevic, Vladana, Kolar-Anić, Ljiljana, "Dynamic transitions in a model of the hypothalamic-pituitary-adrenal axis" in Chaos, 26, no. 3 (2016),
https://doi.org/10.1063/1.4944040 . .

TY  - JOUR
AU  - Marković, Vladimir M.
AU  - Čupić, Željko
AU  - Vukojevic, Vladana
AU  - Kolar-Anić, Ljiljana
PY  - 2011
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/779
AB  - Detailed dynamics of the hypothalamic-pituitary-adrenal (I-IPA) axis is complex, depending on the individual metabolic load of an organism, its current status (healthy/ill, circadian phase (day/night), ultradian phase) and environmental impact. Therefore, it is difficult to compare the HPA axis activity between different individuals or draw unequivocal conclusions about the overall status of the HPA axis in an individual using single time-point measurements of cortisol levels. The aim of this study is to identify parameters that enable us to compare different dynamic states of the HPA axis and use them to investigate self-regulation mechanisms in the HPA axis under acute and chronic stress. In this regard, a four-dimensional stoichiometric model of the HPA axis was used. Acute stress was modeled by inducing an abrupt change in cortisol level during the course of numerical integration, whereas chronic stress was modeled by changing the mean stationary state concentrations of CRH. Effects of acute stress intensity, duration and time of onset with respect to the ultradian amplitude, ultradian phase and the circadian phase of the perturbed oscillation were studied in detail. Bifurcation analysis was used to predict the response of the HPA axis to chronic stress. Model predictions were compared with experimental findings reported in the literature and relevance for pharmacotherapy with glucocorticoids was discussed.
PB  - Japan Endocrine Soc, Kyoto
T2  - Endocrine Journal
T1  - Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress
VL  - 58
IS  - 10
SP  - 889
EP  - 904
DO  - 10.1507/endocrj.EJ11-0037
ER  - 

@article{
author = "Marković, Vladimir M. and Čupić, Željko and Vukojevic, Vladana and Kolar-Anić, Ljiljana",
year = "2011",
abstract = "Detailed dynamics of the hypothalamic-pituitary-adrenal (I-IPA) axis is complex, depending on the individual metabolic load of an organism, its current status (healthy/ill, circadian phase (day/night), ultradian phase) and environmental impact. Therefore, it is difficult to compare the HPA axis activity between different individuals or draw unequivocal conclusions about the overall status of the HPA axis in an individual using single time-point measurements of cortisol levels. The aim of this study is to identify parameters that enable us to compare different dynamic states of the HPA axis and use them to investigate self-regulation mechanisms in the HPA axis under acute and chronic stress. In this regard, a four-dimensional stoichiometric model of the HPA axis was used. Acute stress was modeled by inducing an abrupt change in cortisol level during the course of numerical integration, whereas chronic stress was modeled by changing the mean stationary state concentrations of CRH. Effects of acute stress intensity, duration and time of onset with respect to the ultradian amplitude, ultradian phase and the circadian phase of the perturbed oscillation were studied in detail. Bifurcation analysis was used to predict the response of the HPA axis to chronic stress. Model predictions were compared with experimental findings reported in the literature and relevance for pharmacotherapy with glucocorticoids was discussed.",
publisher = "Japan Endocrine Soc, Kyoto",
journal = "Endocrine Journal",
title = "Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress",
volume = "58",
number = "10",
pages = "889-904",
doi = "10.1507/endocrj.EJ11-0037"
}

Marković, V. M., Čupić, Ž., Vukojevic, V.,& Kolar-Anić, L.. (2011). Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress. in Endocrine Journal
Japan Endocrine Soc, Kyoto., 58(10), 889-904.
https://doi.org/10.1507/endocrj.EJ11-0037

Marković VM, Čupić Ž, Vukojevic V, Kolar-Anić L. Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress. in Endocrine Journal. 2011;58(10):889-904.
doi:10.1507/endocrj.EJ11-0037 .

Marković, Vladimir M., Čupić, Željko, Vukojevic, Vladana, Kolar-Anić, Ljiljana, "Predictive modeling of the hypothalamic-pituitary-adrenal (HPA) axis response to acute and chronic stress" in Endocrine Journal, 58, no. 10 (2011):889-904,
https://doi.org/10.1507/endocrj.EJ11-0037 . .