Immunomodulating Effects of Fungal Beta-Glucans: From Traditional Use to Medicine.

The importance of a well-functioning and balanced immune system has become more apparent in recent decades. Various elements have however not yet been uncovered as shown, for example, in the uncertainty on immune system responses to COVID-19. Fungal beta-glucans are bioactive molecules with immunomodulating properties. Insights into the effects and function of beta-glucans, which have been used in traditional Chinese medicine for centuries, advances with the help of modern immunological and biotechnological methods. However, it is still unclear into which area beta-glucans fit best: supplements or medicine? This review has highlighted the potential application of fungal beta-glucans in nutrition and medicine, reviewing their formulation, efficacy, safety profile, and immunomodulating effects. The current status of dietary fungal glucans with respect to the European scientific requirements for health claims related to the immune system and defense against pathogens has been reviewed. Comparing the evidence base of the putative health effects of fungal beta-glucan supplements with the published guidance documents by EFSA on substantiating immune stimulation and pathogen defense by food products shows that fungal beta-glucans could play a role in supporting and maintaining health and, thus, can be seen as a good health-promoting substance from food, which could mean that this effect may also be claimed if approved. In addition to these developments related to food uses of beta-glucan-containing supplements, beta-glucans could also hold a novel position in Western medicine as the concept of trained immunity is relatively new and has not been investigated to a large extent. These innovative concepts, together with the emerging success of modern immunological and biotechnological methods, suggest that fungal glucans may play a promising role in both perspectives, and that there are possibilities for traditional medicine to provide an immunological application in both medicine and nutrition.

How does scientific information reach the consumer? A case study among students into providing verbal information on dietary supplements at point of purchase.

Consumers of dietary supplements should be made aware of the benefits and risks of these products. This case study therefore aimed to identify the content of the risk-benefit information provided during the purchase of St. John's wort supplements and how consumers perceive this information. Fifteen participants visited a shop to purchase St. John's wort supplements after which they were interviewed on the provided information during the visit. This case study shows that the spontaneous information provision is not consistent in Dutch drugstores and health food shops. The provided information was either very detailed, or no information was given at all. The perceived reliability of information was mainly determined by the authority of the employee and the type of shop where the product was purchased. Information consistency at the moment of purchase is of influence in the perceived value of it.

The Role of Circulating Lycopene in Low-Grade Chronic Inflammation: A Systematic Review of the Literature.

BACKGROUND AND AIMS: In recent years, it has become clear that low-grade chronic inflammation is involved in the onset and progression of many non-communicable diseases. Many studies have investigated the association between inflammation and lycopene, however, results have been inconsistent. This systematic review aims to determine the impact of circulating lycopene on inflammation and to investigate the effect of consuming tomato products and/or lycopene supplements on markers of inflammation. METHODS: Eligible studies, published before March 2020, were identified from PubMed, EBSCOhost and ScienceDirect. Human studies published in English, that evaluated the effect of circulating lycopene in relation to inflammation biomarkers were screened and included. Studies assessing lycopene intake or general intake of carotenoids/antioxidants without measuring circulating lycopene, as well as those not reporting inflammation biomarkers as outcomes, were excluded. RESULTS: Out of 80 publications identified and screened, 35 met the inclusion criteria. Results from 18 cross-sectional studies suggest that lycopene levels are adversely affected during inflammation and homeostatic imbalance. Most of the 17 included intervention studies reported increased circulating lycopene levels after tomato/lycopene supplementation, but almost no changes in inflammation biomarkers were observed. CONCLUSIONS: There is little evidence that increasing tomato intake or lycopene supplementation diminuates this inflammation. However, depletion of lycopene may be one of the first signs of low-grade inflammation. The available data thereby imply that it is beneficial to consume lycopene-rich foods occasionally to stay healthy and keep circulating lycopene at a basal level.

Effects of Monomeric and Oligomeric Flavanols on Kidney Function, Inflammation and Oxidative Stress in Runners: A Randomized Double-Blind Pilot Study.

Nonsteroidal anti-inflammatory drugs are frequently used by athletes in order to prevent musculoskeletal pain and improve performance. In combination with strenuous exercise, they can contribute to a reduction of renal blood flow and promote development of kidney damage. We aimed to investigate whether monomeric and oligomeric flavanols (MOF) could reduce the severity of kidney injuries associated with the intake of 400-mg ibuprofen followed by the completion of a half-marathon in recreational athletes. In this double-blind, randomized study, the original MOF blend of extracts from grape seeds (Vitis vinifera L.) and pine bark (Pinus pinaster L.) or placebo were taken for 14 days preceding the ibuprofen/half-marathon. Urine samples were collected before and after the ibuprofen/half-marathon, and biomarkers of kidney injury, inflammation and oxidative stress were assessed. Intake of MOF significantly reduced the incidence of post-race hematuria (p = 0.0004) and lowered concentrations of interleukin (IL)-6 in the urine (p = 0.032). Urinary neutrophil-associated lipocalin, creatine, albumin, IL-8 and malondialdehyde tended to decrease. The supplementation with MOF in recreational runners appears to safely preserve kidney function, reduce inflammation and promote antioxidant defense during strenuous exercise and intake of a single dose of ibuprofen.

The dietary antioxidant quercetin reduces hallmarks of bleomycin-induced lung fibrogenesis in mice.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, lethal disease of which the etiology is still not fully understood. Current treatment comprises two FDA-approved drugs that can slow down yet not stop or reverse the disease. As IPF pathology is associated with an altered redox balance, adding a redox modulating component to current therapy might exert beneficial effects. Quercetin is a dietary antioxidant with strong redox modulating capacities that is suggested to exert part of its antioxidative effects via activation of the redox-sensitive transcription factor Nrf2 that regulates endogenous antioxidant levels. Therefore, the aim of the present study was to investigate if the dietary antioxidant quercetin can exert anti-fibrotic effects in a mouse model of bleomycin-induced pulmonary fibrogenesis through Nrf2-dependent restoration of redox imbalance. METHODS: Homozygous Nrf2 deficient mice and their wildtype littermates were fed a control diet without or with 800 mg quercetin per kg diet from 7 days prior to a single 1 µg/2 µl per g BW bleomycin challenge until they were sacrificed 14 days afterwards. Lung tissue and plasma were collected to determine markers of fibrosis (expression of extracellular matrix genes and histopathology), inflammation (pulmonary gene expression and plasma levels of tumor necrosis factor-α (TNFα) and keratinocyte chemoattrachtant (KC)), and redox balance (pulmonary gene expression of antioxidants and malondialdehyde-dG (MDA)- DNA adducts). RESULTS: Mice fed the enriched diet for 7 days prior to the bleomycin challenge had significantly enhanced plasma and pulmonary quercetin levels (11.08 ± 0.73 µM versus 7.05 ± 0.2 µM) combined with increased expression of Nrf2 and Nrf2-responsive genes compared to mice fed the control diet in lung tissue. Upon bleomycin treatment, quercetin-fed mice displayed reduced expression of collagen (COL1A2) and fibronectin (FN1) and a tendency of reduced inflammatory lesions (2.8 ± 0.7 versus 1.9 ± 0.8). These beneficial effects were accompanied by reduced pulmonary gene expression of TNFα and KC, but not their plasma levels, and enhanced Nrf2-induced pulmonary antioxidant defences. In Nrf2 deficient mice, no effect of the dietary antioxidant on either histology or inflammatory lesions was observed. CONCLUSION: Quercetin exerts anti-fibrogenic and anti-inflammatory effects on bleomycin-induced pulmonary damage in mice possibly through modulation of the redox balance by inducing Nrf2. However, quercetin could not rescue the bleomycin-induced pulmonary damage indicating that quercetin alone cannot ameliorate the progression of IPF.

Towards improved pharmacotherapy in pulmonary arterial hypertension. Can diet play a role?

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare, progressive disease of the pulmonary vasculature. Recent advances in pharmacotherapy improved life expectancy of PAH patients and, thus, signified the role of general measures, including diet, in the management of the disease. METHODS: In the present narrative review we will briefly summarize information about current and novel PAH therapies and analyze preclinical evidence on the influence of certain nutrients on the pathogenesis of PAH. RESULTS: Although the evidence on the role of dietary deficiencies in the development and progression of PAH in humans is limited, preclinical studies demonstrate that dietary components such as quercetin, genistein, n-3 PUFAs, vitamin D, coenzyme Q10 and resveratrol may influence various aspects of PAH pathobiology. CONCLUSIONS: Further research on the role of diet in PAH is needed. Taking into account pleiotropic and subtle effects of dietary constituents as well as the rare and severe nature of PAH, clinical studies on the disease-specific nutritional patterns rather than on single dietary components may help to reveal if diet can be an important tool to improve the efficacy of pharmacotherapy in PAH.

VKORC1 and CYP2C9 Polymorphisms: A Case Report in a Dutch Family with Pulmonary Fibrosis.

Here, we describe a Dutch family with idiopathic pulmonary fibrosis (IPF). We hypothesized that there might be an association between the presence of Vitamin K epoxide reductase complex 1 (VKORC1) and/or cytochrome P450 2C9 (CYP2C9) variant alleles and the early onset of IPF in the members of this family. VKORC1 (rs9923231 and rs9934438) and CYP2C9 (rs1799853 and rs1057910) were genotyped in this family, which includes a significant number of pulmonary fibrosis patients. In all family members, at least one of the variant alleles tested was present. The presence of the VKORC1 variant alleles in all of the IPF cases and CYP2C9 variants in all but one, which likely leads to a phenotype that is characterized by the early onset and progressive course of IPF. Our findings indicate a role of these allelic variants in (familial) IPF. Therefore, we suggest that the presence of these variants, in association with other pathogenic mutations, should be evaluated during genetic counselling. Our findings might have consequences for the lifestyle of patients with familial IPF in order to prevent the disease from becoming manifest.

International Perspectives on Substantiating the Efficacy of Herbal Dietary Supplements and Herbal Medicines Through Evidence on Traditional Use.

The efficacy of botanicals in medicines can be substantiated with evidence on traditional use, whereas in foodstuffs, this is often not possible. In Europe, for example, the evaluation and subsequent authorization of health claims on herbal dietary supplements (HDS) have been put on hold by the European Commission. This study aims to analyze the role of evidence on traditional use in international legal frameworks of foods and pharmaceuticals. Both legal sources as well as scientific studies offering insights into these regulatory frameworks were included into the analysis. The international approach toward evidence on traditional use for substantiating efficacy of botanicals varies highly. For herbal medicines, substantiating efficacy with evidence on traditional use is possible in all studied jurisdictions, except for Japan and the United States. HDS efficacy can only be substantiated with evidence on traditional use in India and New Zealand, although the enforcing authorities do not describe which data are required. Australia and Canada regulate botanicals in a separate "borderline" category from foods and pharmaceuticals. Both jurisdictions allow for substantiating efficacy with evidence on traditional use. This study's second objective was to assess the applicability of the international approaches in the European legal framework, in light of the ongoing political debate regarding the use of traditional evidence. Implementation of the analyzed international approaches would require major revisions of the current European legal framework. This review of international approaches might, however, aid in deciding upon future approaches for substantiating health claims with evidence on traditional use.

Nutrition and corticosteroids in the treatment of sarcoidosis.

PURPOSE OF REVIEW: Sarcoidosis is a chronic disease, which is routinely treated with corticosteroids. Steroid resistance or steroid-induced adverse effects require alternatives. Other immune-modulating pharmacological treatments have been developed, and therefore expanded tremendously. Until now, the role of nutrition in the overall management of sarcoidosis has been neglected although anti-inflammatory properties of nutritional components have been known for many years now. New nutritional possibilities emerge from already existing data and offer new therapeutic avenues in the treatment of sarcoidosis. RECENT FINDINGS: Various dietary components have been shown to reduce pulmonary inflammatory processes. It is increasingly recognized, however, that the specificity and magnitude of the effect of nutrition differs from pharmacological interventions. Conventional randomized clinical trials are less suitable to test the effect of nutrition in comparison with testing drugs. Mechanistic knowledge on the action of dietary components in conjunction with an increasing understanding of the molecular processes underlying steroid resistance (as investigated in asthma and COPD and unfortunately hardly in sarcoidosis) lead to exciting suggestions on combinations of nutrition/nutritional bioactive compounds and corticosteroids that may benefit sarcoidosis patients. SUMMARY: In order to understand the effects of nutrition in chronic disease, it is important to elucidate mechanisms and pathways of effects. Several complementing lines of evidence should be integrated in order to be able to advise sarcoidosis patients on a healthy diet as such or in combination with prescribed anti-inflammatory therapy.

Dietary supplement intake during pregnancy; better safe than sorry?

Consumption of dietary supplements and specifically niche products such as supplements targeting pregnant women is increasing. The advantages of dietary supplementation during pregnancy with folic acid have been established, but health effects of many other supplements have not been confirmed. EU and US legislation on dietary supplements requires the product to be safe for the direct consumer, the mother. Long-term health effects for the fetus due to fetal programming (in utero adaptation of the fetal epigenome due to environmental stimuli such as supplementation) are not taken into account. Such epigenetic alterations can, however, influence the response to health challenges in adulthood. We therefore call for both conducting research in birth cohorts and animal studies to identify potential health effects in progeny of supplement consuming mothers as well as the establishment of a nutrivigilance scheme to identify favorable and adverse effects post-marketing. The acquired knowledge can be used to create more effective legislation on dietary supplement intake during pregnancy for safety of the child. Increasing knowledge on the effects of consuming supplements will create a safer environment for future mothers and their offspring to optimize their health before, during and after pregnancy.

Pharmacogenetic variants and vitamin K deficiency: a risk factor or trigger for fibrosing interstitial pneumonias?

PURPOSE OF REVIEW: Fibrosing interstitial pneumonias are associated with various stages of fibrosis. The cause of this group of syndromes remains largely unknown. For most of these diseases, a genetic basis, environmental factors and certain triggers have been suggested as possible risk factors. Various studies have found an association between genetic polymorphisms, or the presence of certain variant alleles, and the occurrence and/or progression of interstitial pneumonias of unknown origin. An acute exacerbation of idiopathic pulmonary fibrosis shows characteristics of diffuse alveolar haemorrhage (DAH). DAH can be aggravated by vitamin K deficiency. This review deals with pharmacogenetic factors underlying interindividual differences of vitamin K status in patients with interstitial pneumonias and the possibilities for a personalized approach to patient management. RECENT FINDINGS: DAH has been associated with the presence of variant alleles in vitamin K epoxide reductase complex 1, cytochrome P450 (CYP)2C9 and CYP2C19 genes. Vitamin K deficiency has been associated with an increased risk for the development of DAH and progression and/or deterioration of interstitial pneumonias. This is in line with plausible pathophysiological mechanisms. However, clinical use should be confirmed. SUMMARY: DAH has been associated with vitamin K deficiency and suggested as potential trigger of fibrosing interstitial pneumonias. Information on genetic variation might benefit ongoing/new clinical trials, design of which should reflect needs to address relevance of testing gene variants. Whether vitamin K supplementation may prevent exacerbations or progression of interstitial pneumonias needs to be explored in future studies.

The effects of vitamin E or lipoic acid supplementation on oxyphytosterols in subjects with elevated oxidative stress: a randomized trial.

Despite increased serum plant sterol concentrations after consumption of plant sterol enriched margarines, plasma oxyphytosterol concentrations were not increased in healthy subjects. Here, we assessed plasma oxyphytosterol concentrations and whether they are affected by antioxidants in subjects with elevated oxidative stress. Twenty subjects with impaired glucose tolerance (IGT) or type 2 diabetes (DM2) consumed for 4 weeks placebo, vitamin E (804 mg/d) or lipoic acid capsules (600 mg/d). Plasma and blood cell oxyphytosterol and oxycholesterol concentrations were determined in butylated hydroxytoluene-enriched EDTA plasma via GC-MS. Also, markers reflecting oxidative stress and antioxidant capacity were measured. Plasma oxycampesterol and oxysitosterol concentrations were 122% and 83% higher in IGT or DM2 subjects than in healthy subjects, as determined in an earlier study. Vitamin E or lipoic acid supplementation did not reduce plasma oxyphytosterol and oxycholesterol concentrations, or other markers reflecting oxidative stress or antioxidative capacity. Concentrations of different oxyphytosterols correlated within plasma, and within red blood cells and platelets. However, plasma and blood cell oxyphytosterol levels did not correlate. Although plasma oxyphytosterol concentrations are higher in IGT or DM2 subjects than in healthy subjects, 4-weeks vitamin E or lipoic acid supplementation does not lower plasma oxycholesterol or oxyphytosterol concentrations.

The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function.

Vitamin B6 is a water-soluble vitamin that functions as a coenzyme in many reactions involved in amino acid, carbohydrates and lipid metabolism. Since 2014, >50 cases of sensory neuronal pain due to vitamin B6 supplementation were reported. Up to now, the mechanism of this toxicity is enigmatic and the contribution of the various B6 vitamers to this toxicity is largely unknown. In the present study, the neurotoxicity of the different forms of vitamin B6 is tested on SHSY5Y and CaCo-2 cells. Cells were exposed to pyridoxine, pyridoxamine, pyridoxal, pyridoxal-5-phosphate or pyridoxamine-5-phosphate for 24h, after which cell viability was measured using the MTT assay. The expression of Bax and caspase-8 was tested after the 24h exposure. The effect of the vitamers on two pyridoxal-5-phosphate dependent enzymes was also tested. Pyridoxine induced cell death in a concentration-dependent way in SHSY5Y cells. The other vitamers did not affect cell viability. Pyridoxine significantly increased the expression of Bax and caspase-8. Moreover, both pyridoxal-5-phosphate dependent enzymes were inhibited by pyridoxine. In conclusion, the present study indicates that the neuropathy observed after taking a relatively high dose of vitamin B6 supplements is due to pyridoxine. The inactive form pyridoxine competitively inhibits the active pyridoxal-5'-phosphate. Consequently, symptoms of vitamin B6 supplementation are similar to those of vitamin B6 deficiency.

Masquelier's grape seed extract: from basic flavonoid research to a well-characterized food supplement with health benefits.

Careful characterization and standardization of the composition of plant-derived food supplements is essential to establish a cause-effect relationship between the intake of that product and its health effect. In this review we follow a specific grape seed extract containing monomeric and oligomeric flavan-3-ols from its creation by Jack Masquelier in 1947 towards a botanical remedy and nutraceutical with proven health benefits. The preparation's research history parallels the advancing insights in the fields of molecular biology, medicine, plant and nutritional sciences during the last 70 years. Analysis of the extract's flavanol composition emerged from unspecific colorimetric assays to precise high performance liquid chromatography - mass spectrometry and proton nuclear magnetic resonance fingerprinting techniques. The early recognition of the preparation's auspicious effects on the permeability of vascular capillaries directed research to unravel the underlying cellular and molecular mechanisms. Recent clinical data revealed a multitude of favorable alterations in the vasculature upon an 8 weeks supplementation which summed up in a health benefit of the extract in healthy humans. Changes in gene expression of inflammatory pathways in the volunteers' leukocytes were suggested to be involved in this benefit. The historically grown scientific evidence for the preparation's health effects paves the way to further elucidate its metabolic fate and molecular action in humans.

The potential of flavonoids in the treatment of non-alcoholic fatty liver disease.

The contemporary pathophysiological model of non-alcoholic fatty liver disease (NAFLD) comprises multiple parallel pathways with a dynamic cross talk that cumulate in steatosis and inflammation, and ultimately fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma. So far, no pharmacological treatment has been approved. A major impediment of drugs, in general, is that they are intended to act on one single target in the pathology of a disease. However, the multitude of pathways involved in the pathogenesis of NAFLD underpins the need for treatments that address these various pathways. Interestingly, flavonoids have been found to have positive effects on lipid metabolism, insulin resistance, inflammation, and oxidative stress, the most important pathophysiological pathways in NAFLD. This puts flavonoids in the spotlight for the treatment of NAFLD and prompted us to review the existing evidence for the use of these food-derived compounds in the treatment of NAFLD.

Iron Supplements and Magnesium Peroxide: An Example of a Hazardous Combination in Self-Medication.

The use of self-medication, which includes dietary supplements and over-the-counter drugs, is still on the rise, while safety issues are not well addressed yet. This especially holds for combinations. For example, iron supplements and magnesium peroxide both produce adverse effects via the formation of reactive oxygen species (ROS). This prompted us to investigate the effect of the combination of three different iron supplements with magnesium peroxide on ROS formation. Hydroxyl radical formation by the three iron supplements either combined with magnesium peroxide or alone was determined by performing a deoxyribose assay. Free iron content of iron supplements was determined using ferrozine assay. To determine hydrogen peroxide formation by magnesium peroxide, a ferrous thiocyanate assay was performed. Finally, electron spin resonance spectroscopy (ESR) was performed to confirm the formation of hydroxyl radicals. Our results show that magnesium peroxide induces the formation of hydrogen peroxide. All three iron supplements induced the formation of the extremely reactive hydroxyl radical, although the amount of radicals formed by the different supplements differed. It was shown that combining iron supplements with magnesium peroxide increases radical formation. The formation of hydroxyl radicals after the combination was confirmed with ESR. All three iron supplements contained labile iron and induced the formation of hydroxyl radicals. Additionally, magnesium peroxide in water yields hydrogen peroxide, which is converted into hydroxyl radicals by iron. Hence, iron supplements and magnesium peroxide is a hazardous combination and exemplifies that more attention should be given to combinations of products used in self-medication.

Food-Derived Bioactives Can Protect the Anti-Inflammatory Activity of Cortisol with Antioxidant-Dependent and -Independent Mechanisms.

In chronic inflammatory diseases the anti-inflammatory effect of glucocorticoids (GCs) is often decreased, leading to GC resistance. Inflammation is related with increased levels of reactive oxygen species (ROS), leading to oxidative stress which is thought to contribute to the development of GC resistance. Plant-derived compounds such as flavonoids are known for their ability to protect against ROS. In this exploratory study we screened a broad range of food-derived bioactives for their antioxidant and anti-inflammatory effects in order to investigate whether their antioxidant effects are associated with the ability to preserve the anti-inflammatory effects of cortisol. The anti-inflammatory potency of the tested compounds was assessed by measuring the oxidative stress-induced GC resistance in human macrophage-like cells. Cells were pre-treated with H2O2 (800 µM) with and without bioactives and then exposed to lipopolysaccharides (LPS) (10 ng/mL) and cortisol (100 nM). The level of inflammation was deducted from the concentration of interleukin-8 (IL-8) in the medium. Intracellular oxidative stress was measured using the fluorescent probe 2',7'-dichlorofluorescein (DCFH). We found that most of the dietary bioactives display antioxidant and anti-inflammatory action through the protection of the cortisol response. All compounds, except for quercetin, revealing antioxidant activity also protect the cortisol response. This indicates that the antioxidant activity of compounds plays an important role in the protection of the GC response. However, next to the antioxidant activity of the bioactives, other mechanisms also seem to be involved in this protective, anti-inflammatory effect.

Adverse food-drug interactions.

Food supplements and herbal products are increasingly popular amongst consumers. This leads to increased risks of interactions between prescribed drugs and these products containing bioactive ingredients. From 1991 up to 2014, 55 cases of suspected adverse drug reactions due to concomitant intake of health-enhancing products and drugs were reported to Lareb, the Netherlands Pharmacovigilance Centre. An overview of these suspected interactions is presented and their potential mechanisms of action are described. Mainly during the metabolism of xenobiotics and due to the pharmacodynamics effects interactions seem to occur, which may result in adverse drug reactions. Where legislation is seen to distinct food and medicine, legislation concerning these different bioactive products is less clear-cut. This can only be resolved by increasing the molecular knowledge on bioactive substances and their potential interactions. Thereby potential interactions can be better understood and prevented on an individual level. By considering the dietary pattern and use of bioactive substances with prescribed medication, both health professionals and consumers will be increasingly aware of interactions and these interactive adverse effects can be prevented.

Anticholinergic Accumulation: A Slumbering Interaction between Drugs and Food Supplements.

Many compounds display anticholinergic effects which might give rise to cognitive impairment and even delirium. These side effects are caused by their ability to bind to muscarinic receptors in our brain. Especially with combination of compounds, these serious effects are seen. This phenomenon, known as anticholinergic accumulation, is especially seen in the elderly. A classification of drugs for anticholinergic side effects has been made based on clinical observations, the ACB score. Here, we aimed to substantiate this classification by comparing the affinity of numerous drugs for the muscarinic receptors to the ACB score. Additionally, a number of supplements were screened. The affinity of the compounds was determined by their ability to displace the radioligand [(3)H]pirenzepine of the muscarinic receptor induced by these compounds. Our results show that the affinity of a compound for the muscarinic receptors correlated with its ACB score. Also food supplements appeared to bind to these muscarinic receptors. Moreover, several drug-drug, supplement-supplement and supplement-drug combinations had an affinity that is higher than the affinity of single compounds. This explains the phenomenon of anticholinergic accumulation. In conclusion, care should be taken to drug-drug and supplement-drug combinations with respect to anticholinergic accumulation.

The shifting perception on antioxidants: the case of vitamin E and ß-carotene.

Antioxidants are vital for aerobic life, and for decades the expectations of antioxidants as health promoting agents were very high. However, relatively recent meta-analyses of clinical studies show that supplementation of antioxidants does not result in the presumed health benefit, but is associated with increased mortality. The dilemma that still needs to be solved is: what are antioxidants in the end, healthy or toxic? We have evaluated this dilemma by examining the presumed health effects of two individual antioxidants with opposite images i.e. the "poisonous" ß-carotene and the "wholesome" vitamin E and focused on one aspect, namely their role in inducing BPDE-DNA adducts. It appears that both antioxidants promote DNA adduct formation indirectly by inhibition of the protective enzyme glutathione-S-transferase π (GST π). Despite their opposite image, both antioxidants display a similar type of toxicity. It is concluded that, in the appreciation of antioxidants, first their benefits should be identified and substantiated by elucidating their molecular mechanism. Subsequently, the risks should be identified including the molecular mechanism. The optimal benefit-risk ratio has to be determined for each antioxidant and each individual separately, also considering the dose.