Current Bioactive Compounds - Volume 7, Issue 3, 2011

Mid of the 1980ies, effects of natural compounds with estrogenic activity (phytoestrogens) in humans were discussed for the first time. Due to the discussion about the pros and cons of hormone replacement therapy (HRT) in menopausal and postmenpausal women, phytoestrogens have gained enormous scientific interest during the last two decades. The annual number of publications in this field raised from some thirty about mid of the 90ies to 300 to 400 since 2005. Many studies focussed on the activity of phytoestrogens in the alleviation of menopausal symptoms as well as on their affinity to estrogen receptors. The effects of very different preparations containing these compounds were reported to range between placebo and HRT in the treatment of menopausal complaints. Because of the fact that the three main groups of phytoestrogens (isoflavones, lignans, coumestans) occur in many foodstuffs, numerous food supplements were developed worldwide for the above mentioned indication. Isoflavones from soybeans, soy products, kudzu or red clover, lignans - with the highest concentrations in linseed and in the bran of different cereals - and coumestans e.g. in sprouts of different members of the Leguminosae family, were studied intensively and served as sources for such nutraceuticals. The strongly increasing demand for food supplements rich in phytoestrogens enforced further research: On one hand, their potential for the prevention of so-called “Western diseases” e.g. cardiovascular diseases, hormone dependent cancers, osteoporosis, atherosclerosis, to which estrogen deficiency contributes as well, became a major task in in vitro investigations, animal studies, clinical trials and epidemiologic observations. On the other hand, the analysis of the phytoestrogen content in food supplements attracted reasonable notice. As no proof of quality is required to market such products, analytical methods for the determination became very important with regard to consumer protection. The enormous body of recent literature on the occurrence, analysis, in vitro and in vivo activities and the underlying mechanisms as well as on clinical data and toxicological matters makes it extremely difficult for the reader to stay up-to-date in the field of these compounds. Thus, this issue aims to review three important topics in phytoestrogen research: • Although from long-term epidemiological studies a preventive effect of diets rich in phytoestrogens, like in traditional Asian nutrition, is deduced towards hormone dependent cancer formation, risks of late phytoestrogen exposure are controversially discussed; especially when the compounds are consumed at high conentrations in enriched nutraceuticals without change in the diet. Therefore one review focusses on the lifelong and prenatal effects of phytoestrogen intake.....

Phytoestrogens are highly bioactive compounds that modulate a wide range of signalling pathways. Among these are the aryl hydrocarbon receptor pathway and potential processes that are mediated by an activated aryl hydrocarbon receptor signalling cascade. Isoflavones and indoles have been reported to be dual modulators of the aryl hydrocarbon receptor and the estrogen receptor. The effect of these compounds on the aryl hydrocarbon receptor still requires further investigation, but both in vitro and in vivo studies have demonstrated modulation of this pathway. Implications are difficult to derive because this field requires more research but could include modulation of cell cycle regulation, hormone receptor pathways and reproduction, chemoprevention and cancer, and xenobiotic metabolism. Various studies have presented the aryl hydrocarbon receptor as a modulator of all of these functions, and this could be also caused by isoflavones and indoles as selective aryl hydrocarbon receptor modulators.

In this article an overview of the analytical methods in lignan analysis is given. Sampling, sample preparation (including extraction and hydrolytic sample work up), chromatographic separation methods and several detection modes are discussed and validation parameters like limits of detection and quantitation, recoveries, repeatability and linear range are compared. The challenges of lignan analysis are discussed, advantages and limitations of the individual approaches are described and state of the art methods are presented with main emphasis on sample preparation. Sources of error in sample work-up will be pointed out and recommendations for analysis of lignans in plant foods will be given.

Molecular and cellular effects of lifelong or even multigenerational exposure of phytoestrogens (PEs) are still controversially discussed and gain substantial public attention. While PE-rich diets may be preventive towards menopausal complications as well towards hormone dependent cancer formation, it seems as if late PE exposure at an advanced age results in increased risk of hormonal carcinogenesis in certain animal studies. Long-term epidemiological studies imply a protective effect of PEs on breast tissue as indicated by reduced rates of breast cancer in countries with high consumption of PE-rich soy products, as in Southeast Asia. Although, it is still speculative if the biological effects of soy products derive only from the contained PE. It is known for a number of endocrine modulating substances that the timing of exposure is a crucial element of its final effects. Therefore, exposure during critical developmental windows, such as the embryonal or fetal, the early postnatal and pubertal period, is most likely to have an important impact and result in longest-lasting effects. Thus, these effects may not only result from direct exposure to specific tissues but also by germline modifications. In summary, a number of new studies demonstrate that lifelong PE exposure is able to affect estrogen sensitive tissues, apparently in a tissue selective manner, effects which differ from later life exposure. With respect to health risks and benefits, these data indicates that the situation is much more complex then expected, and these results are highly relevant for the interpretation of regional differences in endocrine-related cancer incidence.

Muramyl dipeptide (MDP) is a synthetic immunoreactive peptide consisting of N-acetyl muramic acid attached to a short amino acid chain of L-Ala-D-isoGln. It was first identified in bacterial cell wall peptidoglycan as an active component in Freund's complete adjuvant. In the cell, MDP is detected by NOD2, a cytoplasmic receptor belonging to the human innate immune system. NOD2 mutations are frequently observed in patients with Crohn's disease, an autoimmune disorder, suggesting the significance of the MDP-NOD2 pathway in activating immunity. For this reason, structural modifications of MDP and its derivatives have been extensively studied in an attempt to increase adjuvant activity and boost the immune response effectively for clinical use in the treatment of cancer and other diseases. This review summarizes the synthetic chemistry of MDP and its derivatives and discusses their pharmacological action and stereoselective synthesis.

The misfolding, aggregation and accumulation of proteins in the brain, represents a common feature of diverse neurodegenerative diseases among which Alzheimer's disease (AD). Important therapeutic strategies for this pathology aim at inhibiting the aggregation of misfolded amyloid β (Aβ) peptides into different species, particularly intermediate oligomeric assemblies, which are believed to be the most neurotoxic species. Here we review the structural data present in the literature, with the purpose to supply useful information for the rational design of new potential molecules able to target Aβ peptides and fibrils. In particular, structural information concerning the different Aβ peptides assemblies, their supramolecular organization, their interaction with cations, biological membranes and known ligands are reported.

Gindarudine (GN), a morphine alkaloid isolated from the tubers of Stephania glabra (Menispermaceae), was evaluated for analgesic and antipyretic activities because of closely resembling structure to that of thebaine. The analgesic activity of GN was evaluated on albino mice by hot plate and tail immersion methods whereas antipyretic activity was studied on Brewer's yeast-induced pyrexia rats. Fever was induced by injecting 20 ml/kg (s.c.) of 20% aqueous suspension of Brewer's yeast in normal saline and rectal temperature was recorded by clinical thermometer immediately before (-18 h) and 18 h after (0 h) yeast administration. GN at doses of 100 and 150 mg/kg, p.o. showed significant analgesic activity (p<0.05) by increasing the threshold potential of pain whereas doses of 200 and 300 mg/kg exhibited significant (p<0.05) antipyretic effect by decreasing the rectal temperature of rats in 1st, 3rd and 5th h after treatment. Aspirin (300 mg/kg, p.o.) and paracetamol (200 mg/kg, p.o.) were used as standard drugs for analgesic and antipyretic activities respectively. These findings demonstrate that GN have remarkable analgesic and anti-pyretic activities when compared with positive control and thus have great potential as a source for natural health products.