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Author: search.filters.author.Radde, NicoleSubject: search.filters.subject.620

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    Analyzing fixed points of intracellular regulation networks with interrelated feedback topology
    (2012) Radde, Nicole
    Modeling the dynamics of intracellular regulation networks by systems of ordinary differential equations has become a standard method in systems biology, and it has been shown that the behavior of these networks is often tightly connected to the network topology. We have recently introduced the circuit-breaking algorithm, a method that uses the network topology to construct a one-dimensional circuit-characteristic of the system. It was shown that this characteristic can be used for an efficient calculation of the system's fixed points. Here we extend previous work and show several connections between the circuit-characteristic and the stability of fixed points. In particular, we derive a sufficient condition on the characteristic for a fixed point to be unstable for certain graph structures and demonstrate that the characteristic does not contain the information to decide whether a fixed point is asymptotically stable. All statements are illustrated on biological network models.
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    Periportal steatosis in mice affects distinct parameters of pericentral drug metabolism
    (2022) Albadry, Mohamed; Höpfl, Sebastian; Ehteshamzad, Nadia; König, Matthias; Böttcher, Michael; Neumann, Jasna; Lupp, Amelie; Dirsch, Olaf; Radde, Nicole; Christ, Bruno; Christ, Madlen; Schwen, Lars Ole; Laue, Hendrik; Klopfleisch, Robert; Dahmen, Uta
    Little is known about the impact of morphological disorders in distinct zones on metabolic zonation. It was described recently that periportal fibrosis did affect the expression of CYP proteins, a set of pericentrally located drug-metabolizing enzymes. Here, we investigated whether periportal steatosis might have a similar effect. Periportal steatosis was induced in C57BL6/J mice by feeding a high-fat diet with low methionine/choline content for either two or four weeks. Steatosis severity was quantified using image analysis. Triglycerides and CYP activity were quantified in photometric or fluorometric assay. The distribution of CYP3A4, CYP1A2, CYP2D6, and CYP2E1 was visualized by immunohistochemistry. Pharmacokinetic parameters of test drugs were determined after injecting a drug cocktail (caffeine, codeine, and midazolam). The dietary model resulted in moderate to severe mixed steatosis confined to periportal and midzonal areas. Periportal steatosis did not affect the zonal distribution of CYP expression but the activity of selected CYPs was associated with steatosis severity. Caffeine elimination was accelerated by microvesicular steatosis, whereas midazolam elimination was delayed in macrovesicular steatosis. In summary, periportal steatosis affected parameters of pericentrally located drug metabolism. This observation calls for further investigations of the highly complex interrelationship between steatosis and drug metabolism and underlying signaling mechanisms.