Sesquiterpene lactone containing Mexican Indian medicinal plants and pure sesquiterpene lactones as potent inhibitors of transcription factor NF-kappaB.

The potential inhibitory effect of 54 Mexican Indian medicinal plants on the activation of transcription factor NF-kappaB was studied. Band-shift experiments identified the ethanolic leaf extracts of Artemisia ludoviciana ssp. mexicana, Calea zacatechichi, and Polymnia maculata (all rich in sesquiterpene lactones) as inhibitors of NF-kappaB down to a concentration of 25 microg/ml. The sesquiterpene lactones isohelenin and parthenolide prevented NF-kappaB activation completely as low as 5 microM. Treatment of HeLa cells with leaf extract of A. ludoviciana ssp. mexicana, isohelenin and parthenolide prevented the induction of transcription on the IL-6 promoter. These experiments identify the eudesmanolide and germacranolide type of sesquiterpene lactones as potent non-antioxidant inhibitors of NF-kappaB. All plants active in the NF-kappaB assay also showed a delay in the onset of capillary reactions of the allantois membrane in a physiological model for anti-inflammatory activity - the HET-CAM assay.

Nahua indian medicinal plants (Mexico): Inhibitory activity on NF-κB as an anti-inflammatory model and antibacterial effects.

Selected plants documented as medicinal in an ethnobotanical study with the Nahua of the Sierra de Zongolica (Veracruz, Mexico) were evaluated for anti-inflammatory and antibacterial activity. One of the potential sides of action of anti-inflammatory drugs is the transcription factor NF-κB. This factor is essential for the immune, inflammatory, and acute phase responses. We therefore tested extracts from a total of 28 plants used by the Nahua Indians for their potential effect on the activation of the transcription factor NF-κB. The leaves of Tithonia diversifolia (Hemsl.) A. Gray (Asteraceae) was the only extract which showed inhibitory activity. Nonspecific DNA binding activities were not noticably influenced. Phytochemical studies to isolate the active principle and further biochemical studies in order to better understand the mode of action of this NF-κB inhibitor have been initiated. Five plants showed noteworthy antibacterial activity against some pathogenic (Staphylococcus aureus ATCC 25933 and Yersinia enterocolitica 03) and nonpathogenic (E. coli DSM 1077, Micrococcus luteus DSM 348) microorganism: Acacia cornigera, Cuscuta tinctoria, Ludwigia octovalvis, Lysiloma divaricata, and Tithonia diversifolia.

Hypericin as a non-antioxidant inhibitor of NF-kappa B.

NF-kappa B is a transcription factor involved in immune and inflammatory responses. Here we show that micromolar concentrations of hypericin inhibited the PMA- and TNF-alpha-induced activation of NF-kappa B in HeLa and TC10 cells, respectively. In contrast, NF-kappa B activated by H2O2 was not influenced by hypericin, indicating a pathway-specificity of hypericin. Hyperforin and a Hypericum perforatum extract standardised on 0.15% hypericin and 5% hyperforin were not active at pharmacologically relevant concentrations. The PMA/TNF-alpha-induced transcription of a reporter gene, which is under the control of the NF-kappa B-dependent IL-6 promoter, was strongly reduced by preincubation with hypericin.

Pheophorbide A from Solanum diflorum interferes with NF-kappa B activation.

Continuing our search for biogenic NF-kappa B inhibitors we investigated Solanum diflorum, used by the Istmo Sierra Zapotec Indians of Mexico in the treatment of inflammatory skin conditions. It became obvious very early that the active substance seems to be a degradation product of chlorophyll. Pheophorbide A was identified as one of the key compounds responsible for the NF-kappa B inhibitory activity. The compound interferes with NF-kappa B activation, was cytotoxic if exposed to light, but devoid of any cytotoxic activity in the dark.

Multiple screening of medicinal plants from Oaxaca, Mexico: ethnobotany and bioassays as a basis for phytochemical investigation.

Based on ethnobotanical data collected among Zapotec Indians in Mexico, nine species traditionally applied to treat skin diseases and two species used to treat gastrointestinal disorders were subjected to several bioassays as further selection criteria for phytochemical investigation. Ten were active against at least one of the pathogenic and/or non-pathogenic bacteria and one against a non-pathogenic fungus in bioautographic TLC and agar diffusion tests. Cytotoxic/antitumor potential was found for one plant species with cell lines (KB, Caco-2) and for six with the brine shrimp assay. In the NF-κB- and the HET-CAM-test used to test for anti-inflammatory potential, two respectively one plant extract showed noteworthy activity. Furthermore, a potentially immunomodulating activity was investigated by evaluating the influence of extracts in various in vitro assays using murine and human lymphoid cells. In addition to the reported biological activities of the eleven plant species, comparisons of the ethnobotanical data and strategies for the selection for further phytochemical investigations are discussed.

Sesquiterpene lactones specifically inhibit activation of NF-kappa B by preventing the degradation of I kappa B-alpha and I kappa B-beta.

Extracts from certain Mexican Indian medicinal plants used in traditional indigenous medicine for the treatment of inflammations contain sequiterpene lactones (SLs), which specifically inhibit the transcription factor NF-kappa B (Bork, P. M., Schmitz, M. L., Kuhnt, M., Escher, C., and Heinrich, M. (1997) FEBS Lett. 402, 85-90). Here we show that SLs prevented the activation of NF-kappa B by different stimuli such as phorbol esters, tumor necrosis factor-alpha, ligation of the T-cell receptor, and hydrogen peroxide in various cell types. Treatment of cells with SLs prevented the induced degradation of I kappa B-alpha and I kappa B-beta by all these stimuli, suggesting that they interfere with a rather common step in the activation of NF-kappa B. SLs did neither interfere with DNA binding activity of activated NF-kappa B nor with the activity of the protein tyrosine kinases p59fyn and p60arc. Micromolar amounts of SLs prevented the induced expression of the NF-kappa B target gene intracellular adhesion molecule 1. Inhibition of NF-kappa B by SLs resulted in an enhanced cell killing of murine fibroblast cells by tumor necrosis factor-alpha. SLs lacking an exomethylene group in conjugation with the lactone function displayed no inhibitory activity on NF-kappa B. The analysis of the cellular redox state by fluorescence-activated cell sorter showed that the SLs had no direct or indirect anti-oxidant properties.