The flavonoid quercetin is frequently found in low amounts as a secondary plant metabolite in fruits and vegetables. Isolated quercetin is also marketed as a dietary supplement, mostly as the free quercetin aglycone, and frequently in daily doses of up to 1000 mg d -1 exceeding usual dietary intake levels. The present review is dedicated to safety aspects of isolated quercetin used as single compound in dietary supplements. Among the numerous published human intervention studies, adverse effects following supplemental quercetin intake have been rarely reported and any such effects were mild in nature. Published adequate scientific data for safety assessment in regard to the long-term use (>12 weeks) of high supplemental quercetin doses (ࣙ1000 mg) are currently not available. Based on animal studies involving oral quercetin application some possible critical safety aspects could be identified such as the potential of quercetin to enhance nephrotoxic effects in the predamaged kidney or to promote tumor development especially in estrogen-dependent cancer. Furthermore, animal and human studies with single time or short-term supplemental quercetin application revealed interactions between quercetin and certain drugs leading to altered drug bioavailability. Based on these results, some potential risk groups are discussed in the present review.

SummaryTNFa-mediated tight junction defects contribute to diarrhea in inflammatory bowel diseases (IBDs). In our study, the signaling pathways of the TNFa effect on barrier-or pore-forming claudins were analyzed in HT-29/B6 human colon monolayers. Berberine, a herbal therapeutic agent that has been recently established as a therapy for diabetes and hypercholesterinemia, was able to completely antagonize the TNFa-mediated barrier defects in the cell model and in rat colon. Ussing chamber experiments and two-path impedance spectroscopy revealed a decrease of paracellular resistance after TNFa to 11±4%, whereas transcellular resistance was unchanged. The permeability of the paracellular marker fluorescein was increased fourfold. Berberine alone had no effect while it fully prevented the TNFa-induced barrier defects. This effect on resistance was confirmed in rat colon. TNFa removed claudin-1 from the tight junction and increased claudin-2 expression. Berberine prevented TNFa-induced claudin-1 disassembly and upregulation of claudin-2. The effects of berberine were mimicked by genistein plus BAY11-7082, indicating that they are mediated via tyrosine kinase, pAkt and NFkB pathways. In conclusion, the anti-diarrheal effect of berberine is explained by a novel mechanism, suggesting a therapeutic approach against barrier breakdown in intestinal inflammation.

Acrolein is an α,β-unsaturated aldehyde formed by thermal treatment of animal and vegetable fats, carbohydrates and amino acids. In addition it is generated endogenously. As an electrophile, acrolein forms adducts with gluthathione and other cellular components and is therefore cytotoxic. Mutagenicity was shown in some in vitro tests. Acrolein forms different DNA adducts in vivo, but mutagenic and cancerogenous effects have not been demonstrated for oral exposure. In subchronic oral studies, local lesions were detected in the stomach of rats. Systemic effects have not been reported from basic studies. A WHO working group established a tolerable oral acrolein intake of 7.5 μg/kg body weight/day. Acrolein exposure via food cannot be assessed due to analytical difficulties and the lack of reliable content measurements. Human biomonitoring of an acrolein urinary metabolite allows rough estimates of acrolein exposure in the range of a few μg/kg body weight/day. High exposure could be ten times higher after the consumption of certain foods. Although the estimation of the dietary acrolein exposure is associated with uncertainties, it is concluded that a health risk seems to be unlikely.

A high intake of fruits and vegetables is associated with a lower risk of cancer. In this context, considerable attention is paid to Asian populations who consume high amounts of soy and soy-derived isoflavones, and have a lower risk for several cancer types such as breast and prostate cancers than populations in Western countries. Hence, interest focuses on soyfoods, soy products, and soy ingredients such as isoflavones with regard to their possible beneficial effects that were observed in numerous experiments and studies. The outcomes of the studies are not always conclusive, are often contradictory depending on the experimental conditions, and are, therefore, difficult to interpret. Isoflavone research revealed not only beneficial but also adverse effects, for instance, on the reproductive system. This is also the case with tumor-promoting effects on, for example, breast tissue. Isoflavone extracts and supplements are often used for the treatment of menopausal symptoms and for the prevention of age-associated conditions such as cardiovascular diseases and osteoporosis in postmenopausal women. In relation to this, questions about the effectiveness and safety of isoflavones have to be clarified. Moreover, there are concerns about the maternal consumption of isoflavones due to the development of leukemia in infants. In contrast, men may benefit from the intake of isoflavones with regard to reducing the risk of prostate cancer. Therefore, this review examines the risks but also the benefits of isoflavones with regard to various kinds of cancer, which can be derived from animal and human studies as well as from in vitro experiments.

TGFβ (isoforms 1-3) has barrier-protective effects in the intestine. The mechanisms involved in regulating tight junction protein expression are poorly understood. The aim of this study was to elucidate TGFβ-dependent protective effects with special attention to promoter regulation of tight junction proteins using the HT-29/B6 cell model. In addition, the effects of whey protein concentrate 1 (WPC1), a natural source of TGFβ in human nutrition, were examined. For this purpose, the claudin-4 promoter was cloned and tested for its activity. It exhibited transactivation in response to TGFβ1, which was intensified when Smad-4 was cotransfected, indicating a Smad-4-dependent regulatory component. Shortening and mutation of the promoter altered and attenuated this effect. WPC1 induced an increase in the claudin-4 protein level and resistance of HT-29/B6 cell monolayers. Anti-TGFβ(1-3) antibodies blocked these whey protein effects, suggesting that a main part of this function was mediated through TGFβ. This effect was observed on intact monolayers as well as when barrier function was impaired by preexposure to IFNγ. In conclusion, TGFβ1 affects claudin-4 gene expression via Smad-4-dependent and -independent transcriptional regulation, resulting in barrier protection, a cytokine effect that is also found in whey protein concentrates used in enteral nutrition.