Dokument: Flavonoide: Quercetin, Kaempferol, Rutin und Fisetin und ihre Effekte im Modellorganismus Caenorhabditis elegans

Titel:Flavonoide: Quercetin, Kaempferol, Rutin und Fisetin und ihre Effekte im Modellorganismus Caenorhabditis elegans
Weiterer Titel:Flavonoids: Quercetin, Kaempferol, Rutin and Fisetin and their effects on model organism Caenorhabditis elegans
URL für Lesezeichen:https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=42698
URN (NBN):urn:nbn:de:hbz:061-20170626-105146-7
Kollektion:Dissertationen
Sprache:Deutsch
Dokumententyp:Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:Text
Autor: Zurawski, Ruben Felix [Autor]
Dateien:
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Dateien vom 20.06.2017 / geändert 20.06.2017
Beitragende:Prof. Dr. Fritz, Gerhard [Gutachter]
PD Dr. rer. nat. Kampkötter, Andreas [Gutachter]
Stichwörter:Caenorhabditis elegans, C. elegans, DAF-16, Fisetin, Flavonoide, Kaempferol, Lebensspanne, lifespan, Quercetin, Rutin, SOD, Superoxiddismutase, Stressresistenz, resistance to stress,
Dewey Dezimal-Klassifikation:600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit
Beschreibungen:Zusammenfassung:

Flavonoide sind in zahlreichen Varianten ubiquitärer Bestandteil pflanzlicher Nahrung. Die Zahl der bekannten Substanzen nimmt stetig zu und parallel mehren sich die wissenschaftlichen Erkenntnisse über positive Effekte einer flavonoidreichen Ernährung. Im Rahmen medizinischer Forschung wird ein positiver Einfluss der Flavonoide, insbesondere auf Erkrankungen des Alters beschrieben. Sie werden in Einzelfällen bereits pharmakologisch genutzt. Die genaue Wirkweise ist jedoch noch in weiten Teilen unklar und nur in einem Bruchteil der bekannten Substanzen untersucht.

Die vorliegende Arbeit untersuchte die Wirkung der Flavonoide Quercetin, Kaempferol, Rutin und Fisetin, die aufgrund ihrer Verbreitung relevante Bestandteile menschlicher Ernährung darstellen.
Mit zellfreien Methoden konnte gezeigt werden, dass alle Testsubstanzen potente Antioxidantien darstellen. Im zweiten Schritt wurde der Einfluss auf Stressresistenz und Lebensspanne des multizellulärer Modellorganismus Caenorhabditis elegans bestimmt. Die mit Quercetin, Kaempferol und Rutin, nicht jedoch die mit Fisetin behandelten Versuchsgruppen zeigten eine erhöhte Resistenz gegen intrazellulären oxidativem Stress. Quercetin verursachte als einzige Substanz eine signifikante Lebensverlängerung unter stressfreien Kulturbedingungen. Ein Zusammenhang mit den radikalfangenden Eigenschaften erscheint naheliegend. Aufgrund der unterschiedlichen Effektstärke und der fehlenden Protektion durch Fisetin, dem stärksten Antioxidanz, ergab sich die Hypothese, dass auch Signalkaskaden relevant beeinflusst wurden.
Mithilfe des transgenen Caenorhabditis elegans Stamm TJ 356 konnte gezeigt werden, dass Flavonoide zu einer Translokation des Transkriptionsfaktors DAF-16 in den Nukleus führen. DAF-16 spielt eine zentrale Rolle in der Regulation von Stressresistenz und Lebensspanne der Modellorganismen. Somit konnte eine Interaktion mit diesem zentralen Signalweg belegt werden, die zudem höchstwahrscheinlich für die zuvor beobachteten Effekte mitverantwortlich war.
Im transgenen Stamm CF 1553 wurden Veränderungen in der Expression des antioxidativen Enzyms SOD-3, einem DAF-16 Zielgen, im lebenden Modellorganismus untersucht. Thermaler und oxidativer Stress führten, im Sinne einer Schutzreaktion, zu einer erhöhten SOD-3-Produktion. Die Flavonoide führten unter stressfreien Bedingungen zu einer Erniedrigung der SOD-3 Expression. Die Erniedrigung trotz DAF-16-Translokation belegt einen Einfluss der Substanzen auf weitere DAF-16 unabhängige SOD-3 regulierende Faktoren. Sie stützt zudem die Hypothese, dass die DAF-16-Translokation Folge einer Interaktion mit Signalwegen war und keine ausschließlich direkte Reaktion auf mögliche prooxidative Effekte der Antioxidantien.

Zusammenfassend konnten für die Mehrzahl der Flavonoide positive Effekt im Modellorganismus belegt werden. Hierbei konnte neben dem antioxidativen Effekt eine Interaktion mit relevanten Signalkaskaden nachgewiesen werden. Die verwendeten Methoden ermöglichten dabei eine zeiteffiziente, vergleichende Bewertung der Testsubstanzen.
Die Ergebnisse stützen die Erkenntnisse zu positive Effekten der Flavonoide im Menschen und nähren die Hoffnung, diese in Zukunft zunehmend gezielt pharmakologisch nutzen zu können.

Abstract:

Flavonoids are compounds that exist in numerous variations ubiquitously in foods of plant origin.
The number of known substances continues to increase. In parallel increasing scientific findings show health beneficial effects of a diet rich of flavonoids.
Results from medical research describe positive influence on age-related diseases. Some flavonoids are being pharmacologically used in specific cases. While it has not been confirmed exactly how these substances work and only a fraction of the substance group was examined more closely.

The current paper examines the effects of the flavonoids Quercetin, Kaempferol, Rutin und Fisetin. All are relevant part of human nourishment.
It was shown that all substances are potent antioxidant in cell-free medium. Influence on stress resistance and lifespan were determined in model organism Caenorhabditis elegans. Trial groups treated with Quercetin, Kaempferol and Rutin showed an increased resistance against intracellular oxidative stress. Trial group treated with Fisetin did not. Only Quercetin caused a significant prolongation of lifespan under stress-free conditions. A connection with the antioxidative activity seems to be plausible.
Due to the different effect sizes and the lack of protection by Fisetin, the strongest antioxidant, the hypothesis was made, that signaling cascades were influenced as well.
It has been demonstrated that Flavonoids cause the change of sub cellular localisation of DAF-16. This was monitored in TJ 356, a transgenic strain of Caenorhabditis elegans. DAF-16 has a pivotal function for regulation of stress resistance and lifespan of the model organism. On the one hand this proves an interaction with such cellular signalling processes. On the other hand it is highly probable a part of the cause of the effects described above.
The expression of the antioxidant enzyme SOD-3 was measured using the transgenic reporter gene strain CF 1553. SOD-3 is a DAF-16 target. Thermal and oxidative stress resulted in an increased production of SOD-3.
The flavonoids led in a decreased expression of SOD-3 under stress-free conditions. The reduction, despite the nuclear translocation of DAF-16, verifies a further impact on other SOD-3 regulation factors. This supports the hypothesis, that the DAF-16 translocation was caused by interactions of flavonoids and signalling pathways and was not a reaction on prooxidative effects of the antioxidants.

The majority of tested flavonoids showed positive effects on the model organism. Besides antioxidative effects, it was possible to reveal an interaction with important signalling pathways. The used methods allowed a time-efficient, comparative analysis of the test substances.
The results support hypothesis of a positive influence of flavonoids on humans. They nourish the hope that they may be used pharmaceutical in future.
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Internetquellen:

Deutsche Gesellschaft für Ernährung e.V.
URL: http://www.dge.de/wissenschaft/weitere Publikationen/fachinformationen/sekundäre-pflanzenstoffe-und-ihre.wirkung [Stand: 10.07.2015]

Molecular Probes Inc.
URL: http://probes.invitrogen.com/media/pis/mp07020.pdf [Stand: 25.11.2010]

National Center for Biotechnology Information, U.S. National Library of Medicine
URL: http://www.ncbi.nlm.nih.gov/pubmed [Stand: 23.11.2010]

The Official Web Site of the Nobel Prize
URL: http://nobelprize.org./nobel_prizes/medicine/laureates/2002/ [Stand 01.07.2010]

Wormatlas.org
URL: http://www.wormatlas.org/hermaphrodite/hermaphroditehomepage.htm
[Stand: 23.11.2010]

Wormbook.org
URL: http://www.wormbook.org/ [Stand: 23.11.2010]
Fachbereich / Einrichtung:Medizinische Fakultät » Institute » Institut für Toxikologie
Dokument erstellt am:26.06.2017
Dateien geändert am:26.06.2017
Promotionsantrag am:04.11.2016
Datum der Promotion:13.06.2017
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