phytoestrogens and 4-oxy-6-(4-oxybezoyloxy)dauc-8-9-en

Ferula hermonis Boiss, is an endemic plant of Lebanon, locally known as "shilsh Elzallouh". It has been extensively used in the traditional medicine as an aphrodisiac and for the treatment of sexual impotence. Crude extracts and isolated compounds of ferula hermonis contain phytoestrogenic substances having a wide spectrum of in vitro and in vivo pharmacological properties including anti-osteoporosis, anti-inflammatory, anti-microbial and anti-fungal, anti-cancer and as sexual activity enhancer. The aim of this mini-review is to highlight the traditional and novel applications of this plant's extracts and its major sesquiterpene ester, ferutinin. The phytochemical constituents and the pharmacological uses of ferula hermonis crude extract and ferutinin specifically will be discussed.

Topics: Animals; Benzoates; Bridged Bicyclo Compounds; Cycloheptanes; Esters; Ferula; Humans; Phytochemicals; Phytoestrogens; Plant Extracts; Sesquiterpenes

The employment studies of natural extracts in the prevention and treatment of several diseases highlighted the role of different species of genus

Topics: Antineoplastic Agents; Antioxidants; Apoptosis; Benzoates; Bridged Bicyclo Compounds; Cell Line, Tumor; Cycloheptanes; Dose-Response Relationship, Drug; Electron Transport; Ferula; Hormone Replacement Therapy; Humans; Mitochondria; Nitric Oxide; Phytochemicals; Phytoestrogens; Plant Extracts; Reactive Oxygen Species; Sesquiterpenes

This study was performed to evaluate the antioxidant, anticancer, and toxicity properties of ferutinin, a phytoestrogen derived from Ferula species. The human Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line and normal human fibroblast (HDF) were cultured and treated with different ferutinin concentrations. The cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell death-defining tests (a comparative real-time polymerase chain reaction [for Bax and Bcl-2 genes], flow cytometry, and acridine orange/propidium iodide cell staining). Moreover, 15 white male balb/c mice were divided into three groups of five (one untreated control group and two groups), which received different doses of ferutinin-supplemented water (500 and 1000 µg/kg mice weight) to check the mice liver and kidney pathomorphological alterations and to determine the antioxidant enzymes' expression profile (superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase) in the mentioned tissues. Finally, the liver lipid peroxidation of mice was analyzed. The results of MTT and cell death-defining tests indicate the significant reduction in cell viability and induction of apoptotic death in MCF-7 cells (enhanced sub-G1 peaks, Bax overexpression, Bcl-2 downregulation, and increased apoptotic cells). The antioxidant enzymes (SOD and CAT) in the mice liver and kidney cells were found to be upregulated (p < .05) in response to the increasing doses of ferutinin. Besides, the lipid peroxidation of the liver tissue of mice was significantly reduced. According to the results, we suggest that ferutinin has the potential to be served as a selective anticancer compound for breast cancer treatment.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antioxidants; Benzoates; Breast Neoplasms; Bridged Bicyclo Compounds; Cycloheptanes; Drug Screening Assays, Antitumor; Female; Ferula; Humans; Male; MCF-7 Cells; Mice; Mice, Inbred BALB C; Phytoestrogens; Sesquiterpenes

The present paper completes our recent study on the effects of phytoestrogen ferutinin in preventing osteoporosis and demonstrating the superior osteoprotective effect of a 2 mg/kg/day dose in ovariectomized (OVX) rats, compared to both estrogens and lower (0.5, 1 mg/kg/day) ferutinin doses. Morphological and morphometrical analyses were performed on the effects of different doses of ferutinin administrated for one month on uterus and on mammary gland of Sprague-Dawley OVX rats, evaluated in comparison with the results for estradiol benzoate. To verify whether ferutinin provides protection against uterine and breast cancer, estimations were made of both the amount of cell proliferation (by Ki-67), and the occurrence of apoptosis (by TUNEL), two processes that in unbalanced ratio form the basis for cancer onset. The results suggest that the effects of ferutinin are dose dependent and that a 2 mg/kg/day dose might offer a better protective action against the onset of both breast and uterine carcinoma compared to ferutinin in lower doses or estradiol benzoate, increasing cellular apoptosis in glandular epithelia.

Topics: Animals; Benzoates; Bridged Bicyclo Compounds; Cycloheptanes; Dose-Response Relationship, Drug; Female; In Situ Nick-End Labeling; Mammary Glands, Animal; Ovariectomy; Phytoestrogens; Rats; Rats, Sprague-Dawley; Sesquiterpenes; Uterus

This study was designed to assess the effect of the phytoestrogenic compound ferutinin, chronically administered in ovariectomized progesterone primed rats, alone or in combination with estradiol benzoate. After 2, 3 and 4 weeks of treatments, female rats were tested for receptive (lordosis) and proceptive behaviors (hops, darts and ear wigglings). Ferutinin given alone markedly increased the intensity of the lordotic response in ovariectomized rats but failed to significantly affect proceptivity. On the other hand estradiol benzoate significantly increased both receptive and proceptive behaviors. When administered in combination with estradiol, ferutinin reduced the increase in receptivity and proceptivity due to estrogen effects, acting as an antiestrogen. At the end of the behavioral experiments, animals were sacrificed and Western blot analysis of estrogen receptor alpha (ERalpha) levels was performed in the dissected hypothalami. Ferutinin increased ERalpha expression when administered alone, as estradiol did, but decreased the response to estradiol when administered in combination. These results suggest that ferutinin displays estrogenic or antiestrogenic activity through ERalpha in the hypothalamus, depending on the absence or the presence of estrogen priming.

Topics: Animals; Benzoates; Bridged Bicyclo Compounds; Cycloheptanes; Estradiol; Estrogen Receptor alpha; Female; Hypothalamus; Male; Ovariectomy; Phytoestrogens; Rats; Rats, Sprague-Dawley; Sesquiterpenes; Sexual Behavior, Animal

The estrogenic activity of a series of analogues of the daucane ester ferutinin (1a) modified at the acyl moiety was investigated in a yeast screen containing the human estrogen receptor alpha. Rather strict structure-activity relationships were observed. Thus, while the parent polyol (jaeschkeanadiol, 2a) was inactive, the presence of a p-hydroxybenzoyl moiety was necessary for activity in the yeast screen. Homologation and vinylation were both detrimental for activity, as were methylation of the p-hydroxyl substituent and the introduction of oxygen functions on the adjacent carbons.

Topics: Benzoates; Binding, Competitive; Bridged Bicyclo Compounds; Cycloheptanes; Dose-Response Relationship, Drug; Esterification; Estrogen Receptor alpha; Estrogens, Non-Steroidal; Female; Ferula; Humans; Isoflavones; Italy; Phytoestrogens; Plant Preparations; Plants, Medicinal; Receptors, Estrogen; Saccharomyces cerevisiae; Sesquiterpenes; Structure-Activity Relationship

Phytoestrogens are assumed to affect the endocrine system of animal species similarly to other man-made endocrine disrupters and to exert their effects through estrogen receptors, specifically ER(alpha) and ERbeta. However, these molecular mechanisms are not fully understood. In this study, 19 phytochemicals were surveyed for agonist and antagonist activities of ER(alpha) and ERbeta using an ERE-luciferase reporter assay. The results showed that ferutinine is an agonist for ER(alpha) and an agonist/antagonist for ERbeta, tschimgine is an agonist for both ER(alpha) and ERbeta, and tschimganidine is an agonist for only ER(alpha). Ferutinine and tschimganidine are sesquiterpenoids, and tschimgine is a monoterpenoid derived from the Umbelliferae family. A competitive binding assay showed that ferutinine has higher binding affinities than tamoxifen for both ERs. Co-transfections of coactivators such as SRC-1, TIF2, AIB1, and TRAP220 in 293T cells and use of the luciferase assay revealed that TRAP220 failed to enhance the transcription mediated by ERbeta in the presence of ferutinine. Moreover, a GST pull-down assay showed that TRAP220 marginally bound to ERbeta ligand binding domain in the presence of ferutinine. These results suggest that the conformation of ferutinine-liganded ERbeta is difficult for TRAP220 to recognize. Taken together, this suggests that some terpenoids can modulate estrogen signaling as ER subtype-selective phytoestrogens similar to SERMs (selective estrogen receptor modulators).

Topics: Apiaceae; Benzoates; Bridged Bicyclo Compounds; Carrier Proteins; Cell Line; Cycloheptanes; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptor Modulators; Estrogens, Non-Steroidal; Genes, Reporter; Humans; Hydroxybenzoates; Isoflavones; Luciferases; Mediator Complex Subunit 1; Phytoestrogens; Plant Preparations; Receptors, Estrogen; Sesquiterpenes; Transcription Factors; Transcription, Genetic; Transcriptional Activation