| Description: |
Helenalin is a promising experimental cytotoxic agent that possibly points to new strategies to overcome apoptosis resistance attributable to overexpression of antiapoptotic Bcl-2 proteins. Helenalin is a new immunosuppressive compound suited for the treatment of deregulated and unwanted T cell-mediated immune responses. Helenalin has anti-inflammatory activity, it inhibits the transcription factor NF-kappaB by directly targeting p65. Helenalin has anti-trypanosomal activity against the African Trypanosoma brucei rhodesiense and American T. cruzi.; it reduces Staphylococcus aureus infection in vitro and in vivo. |
| Targets: |
Bcl-2/Bax | Caspase | P450 (e.g. CYP17) | NF-kB | p65 |
| In vitro: |
| J Biol Chem. 1998 Dec 11;273(50):33508-16. | | The anti-inflammatory sesquiterpene lactone helenalin inhibits the transcription factor NF-kappaB by directly targeting p65.[Pubmed: 9837931] | 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-kappaB, a central mediator of the human immune response. These drugs must target a central step in NF-kappaB pathway, since they inhibit NF-kappaB induction by four different stimuli. It has previously been reported that sesquiterpene lactones exert their effect by inhibiting degradation of IkappaB, the inhibitory subunit of NF-kappaB. These data contradicted our report that IkappaB is not detectable in helenalin-treated, ocadaic acid-stimulated cells.
METHODS AND RESULTS:
Here we use confocal laser scanning microscopy to demonstrate the presence of IkappaB-released, nuclear NF-kappaB in helenalin-treated, tumor necrosis factor-alpha stimulated cells.
CONCLUSIONS:
These data show that neither IkappaB degradation nor NF-kappaB nuclear translocation are inhibited by helenalin. Rather, we provide evidence that helenalin selectively alkylates the p65 subunit of NF-kappaB. This sesquiterpene lactone is the first anti-inflammatory agent shown to exert its effect by directly modifying NF-kappaB. |
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| In vivo: |
| Vet Microbiol. 2007 Jan 31;119(2-4):330-8. | | Helenalin reduces Staphylococcus aureus infection in vitro and in vivo.[Pubmed: 17010538 ] | Staphylococcus (S.) aureus is a major udder pathogen causing bovine mastitis. Some pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), enhance extracellular and intracellular growth of S. aureus, indicating that the inflammatory process favors S. aureus infection. Helenalin is a sesquiterpene lactone with potent anti-inflammatory properties.
METHODS AND RESULTS:
This study was designed to evaluate the effects of Helenalin on S. aureus infection. First, in vitro experiments were conducted. These studies revealed that proliferation of S. aureus in bovine mammary epithelial MAC-T cells treated in the presence or absence of TNF-alpha was markedly reduced in the presence of Helenalin. Secondly, in vivo effects of Helenalin were investigated. Lactating mice treated in the presence or absence of Helenalin were challenged by the intramammary route with S. aureus and the bacteria in the mammary glands were counted 12 h after infection. Significantly less numbers of bacteria were recovered from the infected glands of Helenalin-treated mice compared with untreated mice. Moreover, histological examination of mammary tissue from Helenalin-treated mice that were challenged with S. aureus indicated that Helenalin is able to significantly reduce leukocyte infiltration in the mammary gland following S. aureus inoculation.
CONCLUSIONS:
Our results show that Helenalin reduces S. aureus intracellular growth and experimental S. aureus infection. We conclude that Helenalin may be of potential interest in the treatment of S. aureus-induced mastitis in the bovine species. |
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