Chemical structure of 20-hydroxyecdysone. 

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... the other hand 23 transcripts were correlated between Leuzea and tamoxifen treatments. Most of these genes are in- volved in cell proliferation, DNA replication and apoptosis (such as CCNG2 and TP53N1) and were regulated in an antiprolifera- tive and pro-apoptotic manner. Overall about one third of the genes regulated by Leuzea extract are coding for products in- volved in the regulation of cell proliferation and DNA replication. The vast majority of these transcripts appeared to be down- regulated, consistent with the results of the proliferation assays. Another salient feature was that transcripts coding for enzymes with oxidoreductase activity were highly over-represented among the Leuzea regulated genes. Some genes were strongly up-regulated, such as those of CYP1A1, and, to a lesser extent, CYP1B1. The two oxidoreductases are involved in xenobiotic me- tabolism, mediate toxic and tumorigenic effects of several chem- icals, but are also involved in the metabolism of 17β-estradiol (E2) [27]. CYP1A1 metabolizes E2 to non-carcinogenic 2-hy- droxy-E2 whereas CYP1B1 is responsible for the formation of carcinogenic 4-hydroxy-E2. The two enzymes are not necessari- ly expressed at the same level in tissues. An increased produc- tion of 2-hydroxy-E2 relative to 4-hydroxy-E2, due to a preferen- tial expression of CYP1A1 over CYP1B1, has been suggested to contribute to the antitumor activity of natural compounds such as indole-3-carbinol and is, therefore, of clinical importance [27]. CYP1A1, which was up-regulated up to 130-fold after Leuzea ex- tract treatment, and a handful of other regulated transcripts (CYP1B1, ALDH3A1, ME1, NQO1, TIPARP) are known target genes of the aryl hydrocarbon receptor (AhR), a member of the super- family of nuclear receptors. The AhR, upon binding of a ligand, forms a heterodimeric complex with ARNT (aryl hydrocarbon re- ceptor nuclear translocator) which induces transactivation of the CYPs and other target genes via binding to xenobiotic re- sponse elements (XREs) in their promoter regions [28]. In a XRE-driven luciferase assay in rat hepatoma H4IIE cells Leuzea root extract showed AhR activation comparable to TCDD, a well- RT-PCR measurements were done at least in tripli- cate, means ± SD are presented. RT-PCR measurements were done at least in tripli- cate, means ± SD are presented. known AhR ligand. 20-HE, in contrast, did not induce luciferase activity. Given that classical AhR ligands are hydrophobic and planar or coplanar molecules of polycyclic structure, this nega- tive result for 20-HE is not surprising. The AhR ligands in Leuzea roots are yet to be identified, as there are no obvious candidates among the currently known secondary metabolites of Leuzea (HPLC profiles and a list of identified compounds are given as Supporting Information, Fig. 1S and Table 1S). Via AhR activity of the Leuzea extract the estrogen-like gene ex- pression as well as a decrease of ERα transcript and protein lev- el might be explained. Western blot analysis showed a marked decrease of ERα protein in cells treated with Leuzea extract or E2. The more than additive effect obtained by a simultaneous treatment with extract and E2 suggested a synergistic activity. A decrease of ERα protein content could be either due to down- regulation of transcription or enhanced degradation, as previ- ously described for estradiol treatment [29], [30]. In the pres- ence of E2 a negative cross-talk between the AhR/ARNT com- plex and ligand-bound ERα has been reported, leading to en- hanced proteasome-dependent degradation of both receptors [31]. In the absence of E2, however, ligand-activated AhR/ ARNT heterodimers can activate estrogen receptors and, there- fore, induce expression of ER target genes [32]. This may ex- plain the regulation of estrogen-sensitive transcripts by Leuzea extract. Within the group of oxidoreductases, transcripts coding for AKR1C1 and AKR1C3 (aldo-keto reductase family 1, member C1/3) were up-regulated. The AKR enzymes are known to be in- volved in progesterone metabolism in breast cells. Progester- one is converted by AKRs to 4-pregnene derivatives, which ex- hibit anti-cancer activities [33]. However, the 4-pregnenes and progesterone can be reduced by 5α-reductase to tumor-pro- moting 5α-pregnanes [33], [34]. Reduced activity and mRNA levels of aldo-keto reductases (AKRs) and increased 5α-reduc- tase activity have been found in breast cancer tissue samples and cell lines, resulting in a high ratio of 5α-pregnanes:4-pre- gnenes [34], [35], [36]. Treatments counteracting this dispro- portion, for example, by increased AKR activity and simultane- ously decreased 5α-reductase activity, as observed in our stud- ies with Leuzea root extract in vitro, have been proposed as a new approach in cancer prevention and therapy [34]. Further- more, an increase of 4-pregnene levels following Leuzea treat- ment might also contribute to the ERα decrease described above ...

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... details on the phytochemical profiling of the ex- tract, HPLC chromatograms recorded with PDA, ELSD, and ESIMS detectors, and peak identification are provided as Supporting In- formation (Fig. 1S, Table 1S ). For subsequent experiments, extract and compounds were dis- solved in dimethyl sulfoxide (DMSO) and diluted with appropriate assay media. The final concentration of DMSO did not exceed 0.1 %. This DMSO concentration was also used for control ...

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... carthamoides DC. (syn. Rhaponticum carthamoides [Willd.] Iljin; "maral root"), is a per- ennial Asteraceae plant from the Siberian moun- tain region. Due to its adaptability to rough cli- mates the plant is suited for cultivation as a me- dicinal plant and fodder crop in Northern and Eastern Europe. The roots contain up to 0.6 % phy- toecdysteroids [1], mainly 20-hydroxyecdysone (20-HE) (• " Fig. 1), which are believed to be the ac- tive principles. Additionally, thiophene polyines [2], [3], serotonin derivatives [4], sterols [5] and other minor components have been identified. Dietary supplements derived from Leuzea root extracts, and ecdysteroids, are promoted as anti- aging and adaptogenic (list of products in [6]). In the 1980 s, Russian athletes reportedly used such preparations as "legal doping" due to their puta- tive anabolic action (the use of these products was dubbed as "Russian secret") [7]. Many other beneficial effects such as anti-inflammatory, blood glucose and cholesterol lowering, as well as antitumor activities have been reported in mi- nor publications [6], [8], [9]. Sound pharmacological data about Leuzea root extracts are rare, and little is known about their modes of action. Membrane effects (integration in membrane bilayer and interaction with mem- brane proteins), or binding affinity to various "or- phan" nuclear receptors have been put forward to explain ecdysteroid action in mammals [6], ...