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Anti-inflammatory effects of reactive oxygen species : a multi-valued logical model validated by formal concept analysis

dc.contributor.authorWollbold, Johannesen_ZA
dc.contributor.authorJaster, Roberten_ZA
dc.contributor.authorMuller, Sarahen_ZA
dc.contributor.authorRateitschak, Katjaen_ZA
dc.contributor.authorWolkenhauer, Olafen_ZA
dc.date.accessioned2016-11-02T10:19:19Z
dc.date.available2016-11-02T10:19:19Z
dc.date.issued2014-09
dc.identifier.citationWollbold, J. et al. 2015. Anti-inflammatory effects of reactive oxygen species : a multi-valued logical model validated by formal concept analysis. BMC Systems Biology, 8:101, doi:10.1186/s12918-014-0101-7.
dc.identifier.issn1752-0509 (online)
dc.identifier.otherdoi:10.1186/s12918-014-0101-7
dc.identifier.urihttp://hdl.handle.net/10019.1/99808
dc.descriptionCITATION: Wollbold, J. et al. 2015. Anti-inflammatory effects of reactive oxygen species : a multi-valued logical model validated by formal concept analysis. BMC Systems Biology, 8:101, doi:10.1186/s12918-014-0101-7.
dc.descriptionThe original publication is available at http://bmcsystbiol.biomedcentral.com
dc.description.abstractBackground: Recent findings suggest that in pancreatic acinar cells stimulated with bile acid, a pro-apoptotic effect of reactive oxygen species (ROS) dominates their effect on necrosis and spreading of inflammation. The first effect presumably occurs via cytochrome C release from the inner mitochondrial membrane. A pro-necrotic effect – similar to the one of Ca2+ – can be strong opening of mitochondrial pores leading to breakdown of the membrane potential, ATP depletion, sustained Ca2+ increase and premature activation of digestive enzymes. To explain published data and to understand ROS effects during the onset of acute pancreatitis, a model using multi-valued logic is constructed. Formal concept analysis (FCA) is used to validate the model against data as well as to analyze and visualize rules that capture the dynamics. Results: Simulations for two different levels of bile stimulation and for inhibition or addition of antioxidants reproduce the qualitative behaviour shown in the experiments. Based on reported differences of ROS production and of ROS induced pore opening, the model predicts a more uniform apoptosis/necrosis ratio for higher and lower bile stimulation in liver cells than in pancreatic acinar cells. FCA confirms that essential dynamical features of the data are captured by the model. For instance, high necrosis always occurs together with at least a medium level of apoptosis. At the same time, FCA helps to reveal subtle differences between data and simulations. The FCA visualization underlines the protective role of ROS against necrosis. Conclusions: The analysis of the model demonstrates how ROS and decreased antioxidant levels contribute to apoptosis. Studying the induction of necrosis via a sustained Ca2+ increase, we implemented the commonly accepted hypothesis of ATP depletion after strong bile stimulation. Using an alternative model, we demonstrate that this process is not necessary to generate the dynamics of the measured variables. Opening of plasma membrane channels could also lead to a prolonged increase of Ca2+ and to necrosis. Finally, the analysis of the model suggests a direct experimental testing for the model-based hypothesis of a self-enhancing cycle of cytochrome C release and ROS production by interruption of the mitochondrial electron transport chain.en_ZA
dc.description.urihttp://bmcsystbiol.biomedcentral.com/articles/10.1186/s12918-014-0101-7
dc.format.extent20 pages
dc.language.isoen_ZAen_ZA
dc.publisherBioMed Central
dc.subjectAcute pancreatitisen_ZA
dc.subjectMitochondriaen_ZA
dc.subjectReactive oxygen speciesen_ZA
dc.subjectAnti-inflammatory agentsen_ZA
dc.subjectApoptosisen_ZA
dc.subjectNecrosisen_ZA
dc.titleAnti-inflammatory effects of reactive oxygen species : a multi-valued logical model validated by formal concept analysisen_ZA
dc.typeArticleen_ZA
dc.description.versionPublisher's version
dc.rights.holderAuthors retain copyright


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