Interaction of phytoestrogens with estrogen receptors alpha and beta (II).
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We investigated the estrogenic activities of isoflavone derivatives in competition binding assays with human estrogen receptor (hER) alpha or hER beta protein, and in a gene expression assay using a yeast system. Coumestrol binds as strongly as 17beta-estradiol to both hERs. Biochanin A, 5-OMe-genistein, formononetin, and tectorigenin bind well to hER beta, but significant binding to hER alpha is only observed with 5-OMe-genistein, formononetin and tectorigenin. The binding of 7-OMe-genistein and irisolidone is poor to both receptors. Among the glucosides, sissotorin binds both receptors and the binding is stronger than genistin. Coumestrol induces transcription as strongly as genistein. Tectorigenin also induces transcription with both hERs. Though biochanin A, 5-OMe-genistein, 7-OMe-genistein, irisolidone and formononetin slightly induce transcription with hER beta, they act as antagonists in the induction of transcription by 17beta-estradiol. The results show that methylation or glucosidation of isoflavones generally inhibits their phytoestrogenic activities. (+info)
Effect of tamarind ingestion on fluoride excretion in humans.
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OBJECTIVE: To evaluate the effect of tamarind (Tamarindus indicus) ingestion on excretion of fluoride in school children. DESIGN: Randomized, diet-control study. SUBJECT: Twenty healthy boys were included and 18 of them completed the study. INTERVENTIONS: Each subject consumed 10 g tamarind daily with lunch for 18 days at the social welfare boys' hostel. The nutrient composition of the daily diet was constant throughout the experimental period. RESULTS: Tamarind intake led to significant increase (P<0.001) in the excretion of fluoride in 24 h urine (4.8+/-0.22 mg/day) as compared to excretion on control diet (3.5+/-0.22 mg/day). However, excretion of magnesium and zinc decreased significantly (7.11+/-1.48 mg of Mg and 252.88+/-12.84 microg of Zn per day on tamarind diet as compared to 23.39+/-3.68 mg of Mg and 331.78+/-35.31 microg Zn per day on control diet). Excretion of calcium and phosphorous were not significantly different while creatinine excretion decreased with tamarind intake (225.66+/-81 mg creatinine/day with tamarind and 294.5+/-78.76 mg creatinine/day without tamarind). CONCLUSION: Tamarind intake is likely to help in delaying progression of fluorosis by enhancing urinary excretion of fluoride. (+info)
Modes of membrane interaction of a natural cysteine-rich peptide: viscotoxin A3.
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Among the very homologous family of alpha- and beta-thionins, known for their antimicrobial activity, the viscotoxin subfamily differs from other members because it is cytotoxic against tumoral cells but weakly hemolytic. We studied the interactions between the most active of these toxins, viscotoxin A3 (VA3), and model membranes made of phosphatidylcholine and phosphatidylserine (PS), the major zwitterionic and acidic phospholipids found in eukaryotic cells. Monolayer studies showed that electrostatic forces are essential for the interaction and are mainly involved in modulating the embedding of the toxin in the PS head group region. This in turn induces membrane stiffening, as shown by fluorescence polarization assays with 1,6-diphenyl-1,3,5-hexatriene and its derivatives. Moreover, vesicle permeabilization analyses showed that there are two modes of interaction, which are directly related to the stiffening effect and depend on the amount of VA3 bound to the surface of the vesicles. We propose an interaction model in which the embedding of VA3 in the membrane induces membrane defects leading to the gradual release of encapsulated dye. When the surfaces of the vesicles are saturated with the viscotoxin, complete vesicle destabilization is induced which leads to bilayer disruption, all-or-none encapsulated dye release and rearrangement of the vesicles. (+info)
Antioxidant effects of herbal therapies used by patients with inflammatory bowel disease: an in vitro study.
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BACKGROUND: Herbal remedies used by patients for treatment of inflammatory bowel disease include slippery elm, fenugreek, devil's claw, Mexican yam, tormentil and wei tong ning, a traditional Chinese medicine. Reactive oxygen metabolites produced by inflamed colonic mucosa may be pathogenic. Aminosalicylates (5-ASA) are antioxidant and other such agents could be therapeutic. AIMS: To assess the antioxidant effects of herbal remedies in cell-free oxidant-generating systems and inflamed human colorectal biopsies. METHODS: Luminol-enhanced chemiluminescence in a xanthine/xanthine oxidase cell-free system was used to detect superoxide scavenging by herbs and 5-ASA, and fluorimetry to define peroxyl radical scavenging using a phycoerythrin degradation assay. Chemiluminescence was used to detect herbal effects on generation of oxygen radicals by mucosal biopsies from patients with active ulcerative colitis. RESULTS: Like 5-ASA, all herbs, except fenugreek, scavenged superoxide dose-dependently. All materials tested scavenged peroxyl dose-dependently. Oxygen radical release from biopsies was reduced after incubation in all herbs except Mexican yam, and by 5-ASA. CONCLUSIONS: All six herbal remedies have antioxidant effects. Fenugreek is not a superoxide scavenger, while Mexican yam did not inhibit radical generation by inflamed biopsies. Slippery elm, fenugreek, devil's claw, tormentil and wei tong ning merit formal evaluation as novel therapies in inflammatory bowel disease. (+info)
Estrogen replacement therapy, atherosclerosis, and vascular function.
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There is strong evidence from both human and nonhuman primate studies supporting the conclusion that estrogen deficiency increases the progression of atherosclerosis. More controversial is the conclusion that postmenopausal estrogen replacement inhibits the progression of atherosclerosis. Estrogen treatment of older women (>65 years) with pre-existing coronary artery atherosclerosis had no beneficial effects. In contrast, estrogen treatment of younger postmenopausal women or monkeys in the early stages of atherosclerosis progression has marked beneficial effects. Whether progestogens attenuate the cardiovascular benefits of estrogen replacement therapy has been controversial for more than a decade. Current evidence from studies of both monkeys and women suggest little or no attenuation of estrogen benefits for coronary artery atherosclerosis. Lack of compliance with estrogen replacement therapy, usually because of fear of breast cancer, remains a major problem. Future regimens may overcome that fear by the co-administration of a breast cancer preventive agent (i.e., selective estrogen receptor modulators, phytoestrogens) with low dose estrogen. (+info)
Combined effects of dietary phytoestrogen and synthetic endocrine-active compound on reproductive development in Sprague-Dawley rats: genistein and methoxychlor.
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Humans and wildlife are frequently exposed to mixtures of endocrine active-compounds (EAC). The objective of the present study was to investigate the potential of the phytoestrogen genistein to influence the reproductive developmental toxicity of the endocrine-active pesticide methoxychlor. Three levels of genistein (0, 300, or 800 ppm) and two levels of methoxychlor (0 or 800 ppm) were used in this study. Sprague-Dawley rats were exposed to the two compounds, either alone or in combinations, through dietary administration to dams during pregnancy and lactation and to the offspring directly after weaning. Both compounds, methoxychlor in particular, were associated with reduced body growth at 800 ppm, but pregnancy outcome was not affected by either treatment. An acceleration of vaginal opening (VO) in the exposed female offspring was the only observed effect of genistein at 300 ppm. Exposure to 800 ppm genistein or 800 ppm methoxychlor caused accelerated VO and also altered estrous cyclicity toward persistent estrus in the female offspring. The estrogenic responses to genistein and methoxychlor administered together were apparently accumulative of the effects associated with each compound alone. Methoxychlor, but not genistein, delayed preputial separation (PPS) in the male rats. When administered with methoxychlor, genistein at 800 ppm enhanced the effect of methoxychlor on delaying PPS. Genistein and methoxychlor treatment did not change gender-specific motor activity patterns in either sex. To explore possible mechanisms for interaction between the two compounds on development, we performed estrogen receptor (ER)- and androgen receptor (AR)-based in vitro transcriptional activation assays using genistein and the primary methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). While the in vitro assays supported the estrogenic effects of genistein and methoxychlor and the antiandrogenic effects of methoxychlor, the reactivity of these compounds with ERs alpha and beta could not predict the greater in vivo estrogenic potency of methoxychlor over genistein; nor could the potentiation of the methoxychlor effect on PPS by genistein be predicted based on in vitro HPTE and genistein reactions with the AR. Data from this study indicate that phytoestrogens are capable of altering the toxicological behaviors of other EACs, and the interactions of these compounds may involve complexities that are difficult to predict based on their in vitro steroid receptor reactivities. (+info)
A randomized isoflavone intervention among premenopausal women.
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Isoflavones, phytoestrogens contained in soy foods, may play a role in breast cancer prevention. This randomized double-blinded trial with 34 premenopausal women investigated whether 100 mg of isoflavones per day versus placebo affects the ovulatory cycle during 1 year. Compliance with the study regimen was confirmed by the increase of urinary isoflavone excretion among the intervention group. Blood samples were taken 5 days after ovulation as determined by an ovulation kit, at baseline, and at months 1, 3, 6, and 12. Serum levels of estrone, estradiol, estrone sulfate, progesterone, sex hormone-binding globulin, follicle-stimulating hormone, and luteinizing hormone were quantified by immunoassay; free estradiol was calculated. We applied the method of least squares to fit general linear models to test for an intervention effect while taking into account the repeated measurement design. Except for a small difference in age, the two groups were comparable at baseline. Menstrual cycle length did not change significantly during the intervention [F(1,32) = 0.69; P = 0.44]. During 1 year, we did not observe any significant changes in hormone levels by treatment group. The difference in change between intervention and control group was -13.0 pg/ml (95% confidence interval, -57.5 to 31.5) for estradiol and 6.9 pg/ml (95% confidence interval, -17.8 to 31.5) for estrone. Exclusion of 22 non-ovulatory cycles, noncompliant women, or non-Asian women did not affect the results. These findings do not support the hypothesis that isoflavones affect the ovulatory cycles of premenopausal women over a 1-year period. However, isoflavones alone may have different effects on the reproductive cycle than isoflavones present in soy foods. (+info)
Employment of the human estrogen receptor beta ligand-binding domain and co-activator SRC1 nuclear receptor-binding domain for the construction of a yeast two-hybrid detection system for endocrine disrupters.
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To screen a wide variety of chemicals for endocrine disrupters, and to develop an effective microbial degradation system for them, a good system is needed for the rapid and accurate evaluation of the endocrine-disrupting activities of suspected chemicals and their degradation products. We constructed two-hybrid systems that co-express the Gal4p DNA binding domain/ligand-binding domain of human estrogen receptor (hER) alpha or beta and the Gal4p transactivation domain/nuclear receptor-binding domain of co-activator SRC1, TIF2, or AIB1 in Saccharomyces cerevisiae with a chromosome-integrated lacZ reporter gene under the control of Gal4p-binding sites. We found that the combination of the hERbeta ligand-binding domain and SRC1 nuclear receptor-binding domain was most effective for the xenoestrogen-dependent induction of reporter activity. The extent of transcriptional activation by known xenoestrogens and phytoestrogens was found to correlate well with their estrogenic activities as measured by the previous system with rat ERalpha. This system detects estrogenic activity in some chemicals that have not been suspected of being positive. We also applied this assay system to test the microbial degradation products of gamma-hexachlorocyclohexane (gamma-HCH) by Sphingomonas paucimobilis. Among the gamma-HCH metabolites, 2,5-dichlorohydroquinone and chlorohydroquinone had estrogenic activities similar to the original chemical, while hydroquinone, a later stage metabolite, showed no activity, suggesting the necessity of evaluating intermediate metabolites in microbial degradation systems. (+info)