Dynamic modeling of Nrf2 pathway activation in liver cells after toxicant exposure
Abstract Cells are exposed to oxidative stress and reactive metabolites every day. The Nrf2 signaling pathway responds to oxidative stress by upregulation of antioxidants like glutathione (GSH) to compensate the stress insult and re-establish homeostasis. Although mechanisms describing the interacti...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-05-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-10857-x |
| _version_ | 1817985365855698944 |
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| author | Steven Hiemstra Mirjam Fehling-Kaschek Isoude A. Kuijper Luc J. M. Bischoff Lukas S. Wijaya Marcus Rosenblatt Jeroen Esselink Allard van Egmond Jornt Mos Joost B. Beltman Jens Timmer Bob van de Water Daniel Kaschek |
| author_facet | Steven Hiemstra Mirjam Fehling-Kaschek Isoude A. Kuijper Luc J. M. Bischoff Lukas S. Wijaya Marcus Rosenblatt Jeroen Esselink Allard van Egmond Jornt Mos Joost B. Beltman Jens Timmer Bob van de Water Daniel Kaschek |
| author_sort | Steven Hiemstra |
| collection | DOAJ |
| description | Abstract Cells are exposed to oxidative stress and reactive metabolites every day. The Nrf2 signaling pathway responds to oxidative stress by upregulation of antioxidants like glutathione (GSH) to compensate the stress insult and re-establish homeostasis. Although mechanisms describing the interaction between the key pathway constituents Nrf2, Keap1 and p62 are widely reviewed and discussed in literature, quantitative dynamic models bringing together these mechanisms with time-resolved data are limited. Here, we present an ordinary differential equation (ODE) based dynamic model to describe the dynamic response of Nrf2, Keap1, Srxn1 and GSH to oxidative stress caused by the soft-electrophile diethyl maleate (DEM). The time-resolved data obtained by single-cell confocal microscopy of green fluorescent protein (GFP) reporters and qPCR of the Nrf2 pathway components complemented with siRNA knock down experiments, is accurately described by the calibrated mathematical model. We show that the quantitative model can describe the activation of the Nrf2 pathway by compounds with a different mechanism of activation, including drugs which are known for their ability to cause drug induced liver-injury (DILI) i.e., diclofenac (DCF) and omeprazole (OMZ). Finally, we show that our model can reveal differences in the processes leading to altered activation dynamics amongst DILI inducing drugs. |
| first_indexed | 2024-04-13T23:57:11Z |
| format | Article |
| id | doaj.art-15080c2445a249f3aa5307f2274fe4e7 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-13T23:57:11Z |
| publishDate | 2022-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-15080c2445a249f3aa5307f2274fe4e72022-12-22T02:23:50ZengNature PortfolioScientific Reports2045-23222022-05-0112111010.1038/s41598-022-10857-xDynamic modeling of Nrf2 pathway activation in liver cells after toxicant exposureSteven Hiemstra0Mirjam Fehling-Kaschek1Isoude A. Kuijper2Luc J. M. Bischoff3Lukas S. Wijaya4Marcus Rosenblatt5Jeroen Esselink6Allard van Egmond7Jornt Mos8Joost B. Beltman9Jens Timmer10Bob van de Water11Daniel Kaschek12Division of Drug Discovery and Safety (DDS), Leiden Academic Centre for Drug Research (LACDR), Leiden UniversityInstitute of Physics, University of FreiburgDivision of Drug Discovery and Safety (DDS), Leiden Academic Centre for Drug Research (LACDR), Leiden UniversityDivision of Drug Discovery and Safety (DDS), Leiden Academic Centre for Drug Research (LACDR), Leiden UniversityDivision of Drug Discovery and Safety (DDS), Leiden Academic Centre for Drug Research (LACDR), Leiden UniversityInstitute of Physics, University of FreiburgDivision of Drug Discovery and Safety (DDS), Leiden Academic Centre for Drug Research (LACDR), Leiden UniversityDivision of Drug Discovery and Safety (DDS), Leiden Academic Centre for Drug Research (LACDR), Leiden UniversityDivision of Drug Discovery and Safety (DDS), Leiden Academic Centre for Drug Research (LACDR), Leiden UniversityDivision of Drug Discovery and Safety (DDS), Leiden Academic Centre for Drug Research (LACDR), Leiden UniversityInstitute of Physics, University of FreiburgDivision of Drug Discovery and Safety (DDS), Leiden Academic Centre for Drug Research (LACDR), Leiden UniversityInstitute of Physics, University of FreiburgAbstract Cells are exposed to oxidative stress and reactive metabolites every day. The Nrf2 signaling pathway responds to oxidative stress by upregulation of antioxidants like glutathione (GSH) to compensate the stress insult and re-establish homeostasis. Although mechanisms describing the interaction between the key pathway constituents Nrf2, Keap1 and p62 are widely reviewed and discussed in literature, quantitative dynamic models bringing together these mechanisms with time-resolved data are limited. Here, we present an ordinary differential equation (ODE) based dynamic model to describe the dynamic response of Nrf2, Keap1, Srxn1 and GSH to oxidative stress caused by the soft-electrophile diethyl maleate (DEM). The time-resolved data obtained by single-cell confocal microscopy of green fluorescent protein (GFP) reporters and qPCR of the Nrf2 pathway components complemented with siRNA knock down experiments, is accurately described by the calibrated mathematical model. We show that the quantitative model can describe the activation of the Nrf2 pathway by compounds with a different mechanism of activation, including drugs which are known for their ability to cause drug induced liver-injury (DILI) i.e., diclofenac (DCF) and omeprazole (OMZ). Finally, we show that our model can reveal differences in the processes leading to altered activation dynamics amongst DILI inducing drugs.https://doi.org/10.1038/s41598-022-10857-x |
| spellingShingle | Steven Hiemstra Mirjam Fehling-Kaschek Isoude A. Kuijper Luc J. M. Bischoff Lukas S. Wijaya Marcus Rosenblatt Jeroen Esselink Allard van Egmond Jornt Mos Joost B. Beltman Jens Timmer Bob van de Water Daniel Kaschek Dynamic modeling of Nrf2 pathway activation in liver cells after toxicant exposure Scientific Reports |
| title | Dynamic modeling of Nrf2 pathway activation in liver cells after toxicant exposure |
| title_full | Dynamic modeling of Nrf2 pathway activation in liver cells after toxicant exposure |
| title_fullStr | Dynamic modeling of Nrf2 pathway activation in liver cells after toxicant exposure |
| title_full_unstemmed | Dynamic modeling of Nrf2 pathway activation in liver cells after toxicant exposure |
| title_short | Dynamic modeling of Nrf2 pathway activation in liver cells after toxicant exposure |
| title_sort | dynamic modeling of nrf2 pathway activation in liver cells after toxicant exposure |
| url | https://doi.org/10.1038/s41598-022-10857-x |
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