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  - Stanojevic, A.
AU  - Markovic, V. M.
AU  - Čupić, Željko
AU  - Vukojevic, V.
AU  - Kolar-Anić, Ljiljana
PY  - 2017
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/2254
AB  - A model was developed that can be used to study the effect of gradual cholesterol intake by food on the HPA axis dynamics. Namely, well defined oscillatory dynamics of vital neuroendocrine hypothalamic-pituitary-adrenal (HPA) axis has proven to be necessary for maintaining regular basal physiology and formulating appropriate stress response to various types of perturbations. Cholesterol, as a precursor of all steroid HPA axis hormones, can alter the dynamics of HPA axis. To analyse its particular influence on the HPA axis dynamics we used stoichiometric model of HPA axis activity, and simulate cholesterol perturbations in the form of finite duration pulses, with asymmetrically distributed concentration profile. Our numerical simulations showed that there is a complex, nonlinear dependence between the HPA axis responsiveness and different forms of applied cholesterol concentration pulses, indicating the significance of kinetic modelling, and dynamical systems theory for the understanding of large-scale self-regulatory, and homeostatic processes within this neuroendocrine system.
PB  - Maik Nauka/Interperiodica/Springer, New York
T2  - Russian Journal of Physical Chemistry A
T1  - Modelling of the Hypothalamic-Pituitary-Adrenal Axis Perturbations by Externally Induced Cholesterol Pulses of Finite Duration and with Asymmetrically Distributed Concentration Profile
VL  - 91
IS  - 13
SP  - 2600
EP  - 2607
DO  - 10.1134/S0036024417130027
ER  - 

@article{
author = "Stanojevic, A. and Markovic, V. M. and Čupić, Željko and Vukojevic, V. and Kolar-Anić, Ljiljana",
year = "2017",
abstract = "A model was developed that can be used to study the effect of gradual cholesterol intake by food on the HPA axis dynamics. Namely, well defined oscillatory dynamics of vital neuroendocrine hypothalamic-pituitary-adrenal (HPA) axis has proven to be necessary for maintaining regular basal physiology and formulating appropriate stress response to various types of perturbations. Cholesterol, as a precursor of all steroid HPA axis hormones, can alter the dynamics of HPA axis. To analyse its particular influence on the HPA axis dynamics we used stoichiometric model of HPA axis activity, and simulate cholesterol perturbations in the form of finite duration pulses, with asymmetrically distributed concentration profile. Our numerical simulations showed that there is a complex, nonlinear dependence between the HPA axis responsiveness and different forms of applied cholesterol concentration pulses, indicating the significance of kinetic modelling, and dynamical systems theory for the understanding of large-scale self-regulatory, and homeostatic processes within this neuroendocrine system.",
publisher = "Maik Nauka/Interperiodica/Springer, New York",
journal = "Russian Journal of Physical Chemistry A",
title = "Modelling of the Hypothalamic-Pituitary-Adrenal Axis Perturbations by Externally Induced Cholesterol Pulses of Finite Duration and with Asymmetrically Distributed Concentration Profile",
volume = "91",
number = "13",
pages = "2600-2607",
doi = "10.1134/S0036024417130027"
}

Stanojevic, A., Markovic, V. M., Čupić, Ž., Vukojevic, V.,& Kolar-Anić, L.. (2017). Modelling of the Hypothalamic-Pituitary-Adrenal Axis Perturbations by Externally Induced Cholesterol Pulses of Finite Duration and with Asymmetrically Distributed Concentration Profile. in Russian Journal of Physical Chemistry A
Maik Nauka/Interperiodica/Springer, New York., 91(13), 2600-2607.
https://doi.org/10.1134/S0036024417130027

Stanojevic A, Markovic VM, Čupić Ž, Vukojevic V, Kolar-Anić L. Modelling of the Hypothalamic-Pituitary-Adrenal Axis Perturbations by Externally Induced Cholesterol Pulses of Finite Duration and with Asymmetrically Distributed Concentration Profile. in Russian Journal of Physical Chemistry A. 2017;91(13):2600-2607.
doi:10.1134/S0036024417130027 .

Stanojevic, A., Markovic, V. M., Čupić, Željko, Vukojevic, V., Kolar-Anić, Ljiljana, "Modelling of the Hypothalamic-Pituitary-Adrenal Axis Perturbations by Externally Induced Cholesterol Pulses of Finite Duration and with Asymmetrically Distributed Concentration Profile" in Russian Journal of Physical Chemistry A, 91, no. 13 (2017):2600-2607,
https://doi.org/10.1134/S0036024417130027 . .

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 . .