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Weidong Zhang - One of the best experts on this subject based on the ideXlab platform.

Yun Heng Shen - One of the best experts on this subject based on the ideXlab platform.

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Irmgard Merfort - One of the best experts on this subject based on the ideXlab platform.

  • surface plasmon resonance analysis of nuclear factor κb protein interactions with the Sesquiterpene Lactone helenalin
    Analytical Biochemistry, 2010
    Co-Authors: Berthold Buchele, Irmgard Merfort, Waltraud Zugmaier, Oleg Lunov, Tatiana Syrovets, Thomas Simmet
    Abstract:

    Sesquiterpene Lactones such as helenalin have generally been considered as highly promising compounds for the treatment of inflammatory disorders. Although Sesquiterpene Lactones are known to inhibit signaling through transcription factor nuclear factor-kappaB (NF-kappaB), the nature of their molecular targets remains controversial. To characterize the interactions of helenalin with putative target proteins, a surface plasmon resonance-based method was developed and validated to analyze the interactions of helenalin with the NF-kappaB protein p65/RelA, with recombinant IkappaB kinases (IKKs) alpha and beta, and with the intracellular antioxidant glutathione, all immobilized on sensor chips. At pH 7.4, helenalin is interacting with RelA (K(D)=4.8microM), yet it failed to bind either IKKalpha or IKKbeta. When DNA with NF-kappaB binding sites was immobilized on sensor chips, the binding of RelA was inhibited by helenalin with an IC(50) of 5.0microM. At pH 8.0, helenalin was also able to interact with reduced, but not oxidized, glutathione with a K(D) of 24microM, but no significant interaction was observed at pH 7.4. Thus, with this optimized method, we showed that the Sesquiterpene Lactone helenalin interacts with the NF-kappaB protein RelA but not with IKKalpha or IKKbeta. Moreover, at physiological pH, helenalin does not interact with glutathione to any significant extent.

  • the anti inflammatory Sesquiterpene Lactone helenalin inhibits the transcription factor nf κb by directly targeting p65
    Journal of Biological Chemistry, 1998
    Co-Authors: Guido Lys, Heike L Pahl, Thomas J. Schmidt, Alexander Knorre, Irmgard Merfort
    Abstract:

    The Sesquiterpene Lactone helenalin is a potent anti-inflammatory drug whose molecular mechanism of action remains unclear despite numerous investigations. We have previously shown that helenalin and other Sesquiterpene Lactones selectively inhibit activation of the transcription factor NF-κB, a central mediator of the human immune response. These drugs must target a central step in NF-κB pathway, since they inhibit NF-κB induction by four different stimuli. It has previously been reported that Sesquiterpene Lactones exert their effect by inhibiting degradation of IκB, the inhibitory subunit of NF-κB. These data contradicted our report that IκB is not detectable in helenalin-treated, ocadaic acid-stimulated cells. Here we use confocal laser scanning microscopy to demonstrate the presence of IκB-released, nuclear NF-κB in helenalin-treated, tumor necrosis factor-α stimulated cells. These data show that neither IκB degradation nor NF-κB nuclear translocation are inhibited by helenalin. Rather, we provide evidence that helenalin selectively alkylates the p65 subunit of NF-κB. This Sesquiterpene Lactone is the first anti-inflammatory agent shown to exert its effect by directly modifying NF-κB.