Food Components in Health Promotion and Disease Prevention

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Food Components in Health Promotion and Disease Prevention Wolfgang Langhans* Physiology and Behavior Laboratory, Institute of Food, Nutrition and Health, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland ABSTRACT: The current obesity epidemic with its deleterious effects on public health and the increase in the prevalence of non-communicable diseases in our aging society have dramatically increased public awareness of nutrition-related health issues. On one hand, food components, such as fat, sugar, flavors, and spices, are major determinants of the hedonic value of food, and the constant and almost ubiquitous availability of good-tasting food in our affluent societies promotes overeating and weight gain. On the other hand, several food components, including flavoring compounds and the active ingredients of many plants, such as spices and herbs (e.g., polyphenols and capsaicinoids) or thylakoids, supposedly can decrease food intake and affect gastrointestinal function and metabolism. These substances may act as antioxidants, may stimulate the release of incretins and, hence, insulin, and may improve insulin sensitivity or decrease plasma levels of lipids. Such beneficial effects are often difficult to demonstrate in epidemiological studies because they may occur only at supraphysiological doses and/or when the purified compounds are administered, but they can be present under certain circumstances. This review discusses the putative mechanisms of the health-promoting and disease-preventing effects of some food components and their potential physiological relevance, primarily with respect to counteracting obesity and type 2 diabetes. KEYWORDS: Western diet, polyphenols, thylakoids, dashi

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INTRODUCTION Obesity has reached endemic proportions. This fact together with the multiple severe comorbidities of obesity [e.g., cardiovascular disease (CVD), type 2 diabetes (T2D), joint problems, and some cancers] and the general demographic change with an ever-increasing average age of the population have also enhanced public awareness of the increase in the incidence of non-communicable and, in particular, nutritionrelated diseases. T2D and CVD as well as joint problems resulting from overweight and adiposity, on one hand, and of the demographic change, on the other hand, challenge health care systems worldwide. Whereas aging itself cannot be prevented, its impact and negative consequences can be reduced; i.e., age-related diseases and health problems can be prevented to some degree or be delayed, and obesity is preventable, too. The fact is that almost all of the diseases that constitute the major causes for premature death in industrialized countries (http://vizhub.healthdata.org/gbd-compare/) or disability-adjusted life years are attributable to certain behavioral and metabolic risk factors. On the behavioral side, it is primarily dietary habits, low physical activity, smoking and alcohol consumption, and on the metabolic side, it is high blood pressure, obesity, and T2D. Our Western diet is profoundly unhealthy:1 On one hand, we eat too much red and processed meat, too much sugar and simple carbohydrates, too much saturated fats, and too much salt. On the other hand, certain micronutrient deficiencies are common even in industrialized countries; examples are folate, iodine, iron, or vitamin D3 deficiencies. To make things worse, the positive economic development with the global rises in personal income and urbanization fuel a continuous increase in the per capita demand for meat protein, refined sugars, and refined fats around the world. This global dietary transition, on one hand, contributes to the obesity endemic with its consequences,2 and © XXXX American Chemical Society

on the other hand, the adoption of the unhealthy Western diet in more and more counties around the globe is not sustainable.1 These developments raise the question why do we not just change our dietary pattern? Why do we not eat a healthier and more sustainable diet? The answer is simple: We do not do it because good-tasting and, in particular, high-caloric food is just too rewarding and because maximizing the sensory pleasure is a major incentive for any behavior, including eating.3 In other words, often we eat because hedonic factors prompt us to do so, even if we are not hungry. The ability to respond to attractive food by spontaneous overeating certainly carried an evolutionary advantage because it increased the chances of our ancestors to survive a subsequent period during which adequate food was lacking. In our current obesogenic environment, however, this capacity to overeat when encountering attractive food options certainly contributes to the development of obesity because, nowadays, at least in our Western societies, the overeating is not followed by periods without adequate food access; rather, the presence of good-tasting attractive food is ubiquitous and permanent. Studies in which researchers asked people “what do you consider important in relation to nutrition” and compared the responses to answers to the question “what is important when you eat”4 emphasize the relevance of hedonic eating under normal life situations. The results of these studies commonly show that average lay people, at least in Europe, actually know Special Issue: 11th Wartburg Symposium on Flavor Chemistry and Biology Received: Revised: Accepted: Published: A

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against particular gustatory and olfactory stimuli control food selection.7 Almost all mammals display an innate preference for sweet and an innate aversion against bitter taste, but these innate preferences and aversions are of course modifiable. In fact, food selection is primarily controlled by learned preferences and aversions.8 A complex neuronal network with nodes in the hindbrain, the diencephalon, and the forebrain processes all of the peripheral signals and ensures the adaptability of the whole control system to changes in the environment and physiological state.6 As mentioned above, the constant and virtually ubiquitous availability of attractive, goodtasting food in our current obesogenic environment promotes the development of overweight and obesity, despite this effective physiological control system. This is because, for our ancestors, it was essential being able to react to the sudden availability of attractive food sources by overeating.9 Food components can influence this feedback system that controls eating in various ways: Complex carbohydrates, for instance, delay gastrointestinal transit and can, thus, inhibit eating and reduce body weight10,11 in addition to their other beneficial effects on health (mitigation of T2D, CVD, hyperlipidemia, etc.). Some of these effects are related to the delay of glucose absorption, which dampens the postprandial rise in blood glucose; it also prevents reactive hypoglycemia, which might have the potential to even further stimulate eating. Complex carbohydrates also influence the composition of the gut microbiota, which influences eating through changes in the production of short-chain fatty acids and systemic concentrations of satiating gut peptides.12 Other food components increase palatability (sugar, herbs, spices, etc.) and can, therefore, potentially contribute to overeating in our obesogenic environment. This is of course particularly true for sugar because sweet taste has an especially pronounced rewarding effect.13 Food components that increase palatability can, however, also activate various mechanisms of satiation and satiety and, hence, have an overall beneficial effect with respect to obesity and metabolism.

fairly well what they should do; i.e., they know they should eat less saturated fat, less sugar, less salt, etc. In other words, the nutritional knowledge is there, but when we sit down and eat, this nutritional knowledge barely influences behavior because hedonic factors and the pursuit of pleasure, i.e., good taste and a nice atmosphere in a cozy environment, drive behavior. This makes of course any attempt to influence behavior with purely rational arguments very difficult. “Nudging” consumers toward healthier choices by various means is one alternative approach that may hold some promise.5

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ROLE OF FOOD COMPONENTS Despite these seemingly unfavorable preconditions, however, it is clear that preventive measures are particularly relevant and efficient for non-communicable diseases. In addition to regular exercise, a healthy nutrition is an essential part of any prevention. What and how much we eat influences our body in many ways. The macronutrients and their breakdown products but also other food ingredients, on one hand, directly affect nutrient digestion, intermediary metabolism, and organ functions; on the other hand, food ingredients can modify food intake and, hence, indirectly affect body weight, with the ensuing effects on health. More specifically, certain food ingredients, e.g., herbs and spices, can, on one hand, stimulate food intake by enhancing the hedonic attractiveness of the food eaten, which can at least indirectly promote weight gain, but on the other hand, they can have a direct beneficial effect on health through diverse mechanisms. Thus, plant-derived substances, such as complex carbohydrates, polyphenols/flavonoids, carotinoids, catechines, etc., and other food components can inhibit eating and modulate gastrointestinal function (e.g., gastrointestinal transit, the release of digestive enzymes, bile secretion, and bile flow). In addition, many substances influence metabolism by acting as antioxidants or stimulating the release of incretins and, hence, insulin from the pancreatic beta cells; some of these substances also improve insulin sensitivity at the level of the target tissues or reduce the plasma concentrations of lipids. At the molecular level, many of these effects appear to be related to an activation of AMP-activated protein kinase (AMPK) or a modulation of several transcription factors, such as the nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor κB (NFκB), p21, and others. In this review, I will first briefly present a summary of the neuroendocrine mechanisms that control eating. Then, I will select a few examples of food components and discuss their putative health-promoting and disease-preventing effects and the underlying physiological mechanisms as well as their possible therapeutic potential.

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POLYPHENOLS General. The active ingredients of many herbs and spices are polyphenols, bioactive substances that are virtually omnipresent in plant-derived foods. They constitute a group of more than 500 compounds with different chemical structures.14 The literature concerning the health-promoting effects of polyphenols is huge.14,15 Here, I will therefore restrict myself to some examples, mainly with respect to the influence of individual polyphenols on CVD, eating, metabolism, adiposity, and T2D. Cell culture, in vitro and in vivo studies in animals and humans report beneficial effects, in particular, for resveratrol, curcumin, green tea [epigallocatechin (EGCG) and green tea extracts (GTEs)], hydroxytyrosol, and capsaicinoids, in particular, capsaicin.14,16,17 Resveratrol. Resveratrol (3,4′,5-trihydroxystilbene) is a polyphenolic compound produced by certain plants in response to stress, injury, fungal infection, or ultraviolet (UV) radiation.18,19 It is fat-soluble and occurs in both trans and cis molecular configurations. One major resveratrol derivative is resveratrol-3-O-β-glucoside, also called piceid.20 Resveratrol has been proposed to have antioxidant and anti-inflammatory properties, to improve glucose homeostasis and lipid metabolism, and to upregulate endothelial nitric oxide synthase.18 NO causes vasodilation and decreases platelet aggregation, leukocyte recruitment, and smooth muscle cell

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CONTROL OF EATING A physiological feedback loop controls eating; in this loop, feedback signals from the gastrointestinal tract as well as from intermediary metabolism determine the onset and end of individual meals.6 In addition, hormones that reflect the size and presumably also the dynamic changes of the fat depots modulate the meal-related short-term signals commensurate with the available fat (=the most important energy store of the body).6 It is important to note, in this context, that this part of the energy balance regulation is primarily operative and efficient when food is lacking, i.e., in a state of underweight, but relatively inefficient and unable to prevent the development of obesity when food is plenty.6 Preferences for and aversions B

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Journal of Agricultural and Food Chemistry proliferation,21 thus potentially preventing atherosclerosis. Pertinent studies also identified other possible molecular mediators (SIRT-1, AMPK, Nrf2, NFκB, p21, etc.) of the health-promoting effects of resveratrol.18 In addition, resveratrol affects gene expression through epigenetic effects.22,23 These may contribute to several of its proposed actions, including its anticancer effect.24 It needs to be emphasized, however, that most of the studies suggesting health-promoting effects for resveratrol were performed in cell culture systems or laboratory animal models that are not necessarily relevant for humans.25 Only in one randomized, double-blind, placebocontrolled clinical trial, the oral administration of a resveratrolrich grape supplement in individuals at high risk for CVD reduced the plasma concentration of inflammatory markers and other CVD-risk markers.26 There are, however, only very few such clinical trials in humans, and the concentrations and doses used in the in vitro and preclinical animal studies were often well above what can be reached in humans consuming resveratrol orally.25,27 The major problem in this context is the unfavorable pharmacodynamics. While resveratrol, in particular, trans-resveratrol, is fairly well-absorbed from the intestine, its bioavailability is relatively low because it is rapidly metabolized and eliminated through the kidneys,28 mainly in the form of sulfate and/or sulfoglucuronides. In addition, there are scarcely any clinical safety trials, and some reports suggest the possibility of toxicity at very high levels of intake.29,30 Therefore, clinical trials carefully designed on the basis of a thorough analysis of resveratrol pharmacology and biology are needed to conclusively answer the question of whether resveratrol may eventually turn out to be a “promising therapeutic or a hopeless illusion”.25 Curcumin. Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is the major polyphenol found in the rhizome of Curcuma longa (turmeric), which is a member of the ginger family.31 Curcumin has been traditionally used in India and other Asian countries to treat several diseases.32 Also, curcumin has been proposed to have antioxidant, antiinflammatory, antimutagenic, antimicrobial, and anticancer properties.33 The antioxidant and anti-inflammatory effects have also been implicated in the putative antidiabetic action of curcumin.34 In one study designed to investigate the effect of curcumin on liver metabolism in mice fed a high-fat diet, curcumin reduced body weight, adiposity, total cholesterol, fasting glucose, and insulin in serum as well as improved insulin sensitivity and reduced hepatic fat accumulation.35 These effects appeared to be due to an activation of AMP kinase and the subsequent improvement of hepatic lipid metabolism.35 Some of the antioxidant effects of curcumin are related to the induction of the expression of antioxidant enzymes, including glutamate−cysteine ligase,36 the rate-limiting enzyme in the synthesis of glutathione (GSH), an important intracellular antioxidant. The anti-inflammatory effects of curcumin result in large part from its ability to inhibit the NF-κB and other proinflammatory pathways.37 A major problem also with curcumin is, however, that its bioavailability after oral consumption or administration is low38 because it is poorly absorbed and rapidly metabolized. Some evidence indicates that, after oral administration, curcumin accumulates in gastrointestinal tissues, suggesting that the action of curcumin may be primarily in the gastrointestinal tract.39 Nevertheless, there are some randomized controlled trials in which beneficial effects of highdose curcumin supplementation (usually >1 g/day) in humans have been observed on circulating levels of adipokines40 and

pro-inflammatory cytokines41 or circulating triglycerides.42 Although these studies did not report systemic curcumin concentrations, the results suggest the possibility of some systemic beneficial effects of high-dose oral curcumin supplementation. Thus, also for curcumin, some of the beneficial effects mentioned above were observed in cell culture and laboratory animal studies with concentrations and doses of curcumin that are unlikely to be achieved in target tissues of humans after oral consumption; but some beneficial effects may be possible with high-dose supplementation. Epigallocatechin (EGCG) and Green Tea Extracts (GTEs). For green tea, the leaves of the Camellia sinensis plant are steamed or fired to inactivate polyphenol oxidase before they are dried. This ensures that the polyphenol content of green tea is much higher than that of black tea. Green tea contains several bioactive compounds, including caffeine and fluoride, but with respect to the potential health beneficial effects, most research has focused on the polyphenolic components (flavonoids) that green tea contains, i.e., on epicatechin, epicatechin gallate, and epigallocatechin, in particular, epigallocatechin-3-gallate (EGCG).15,43 Epidemiological studies in humans suggest an inverse relationship between green tea consumption and the development of CVD, including coronary heart disease and stroke;44 i.e., an increase in green tea consumption appears to decrease the risk of CVD. Green tea extracts have also been reported to increase energy expenditure15,45 and reduce body weight.15,43,45 The caffeine content of green tea may contribute to this effect, but it is clear that green tea or GTEs have a thermogenic and body weight effect that goes beyond any effect of caffeine. The mechanisms of the health-promoting effects of EGCG and GTEs are still not fully clear. Several lines of evidence indicate, however, that an inhibition of the absorption of fat in the intestine15,46 and a stimulation of fatty acid oxidation,15,46 presumably mediated by an activation of AMP kinase in different tissues,46 contribute. In addition and similar to resveratrol, EGCG appears to affect gene expression through epigenetic effects, in particular, through its profound inhibitory effect on DNA methyl transferases and, hence, DNA methylation.22 This mechanism could be particularly relevant for the proposed anticancer effect of GTEs.22 It should be mentioned that France and Spain banned some GTEs because of potential liver toxic effects. This decision is, however, not undisputed (see refs 47 and 48), and the potential liver toxic effects of high doses of some GTEs are currently under renewed European Food Safety Authority (EFSA) scrutiny. EFSA expects to complete the assessment and publish the results toward the end of 2017. Hydroxytyrosol (HT). The fruit and leaves of the olive tree (Olea europaea) contain several polyphenols, including HT [2(3,4-dihydroxyphenyl)-ethanol], which is the major phenolic component of olive oil. HT is certainly not the most intensely investigated polyphenol that supposedly promotes health, but it is considered to be the major contributor to the various health beneficial effects of a Mediterranean diet. In recent years, evidence for health beneficial effects of HT has accumulated. Anti-inflammatory, anticarcinogenic, antiapoptotic, and neuroprotective effects have been reported.49 Most of these effects are supposedly related to the antioxidant properties of HT. In fact, HT appears to have the strongest in vitro antioxidant potential of all phenolic compounds in olive oil.50 The anticarcinogenic effects of HT and other phenolic compounds in olive oil, for instance, are most likely due to a reduction in DNA damage, resulting in an inhibition of both initiation and C

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GARCINIA CAMBOGIA AND HOODIA GORDONII Other plant-derived substances or substance mixtures with a presumed beneficial effect on health are the extracts of G. cambogia62 and H. gordonii.63 G. cambogia is a mixture of alkaloids, polyphenols (e.g., xanthones), organic acids (e.g., hydroxycitric acid), amino acids, and other substances;62 for H. gordonii, the glycoside P57 was isolated as the major principle of action,63 alone or together with its aglycone hoodigogenin A (also hoodigonin or gordonoside A), resulting from extensive gastric breakdown of P57. G. cambogia has traditionally been used as a spice for fish curries. More recently, it has been widely advertised as a weight-loss supplement based on the results from studies showing that extracts of G. cambogia exhibited antiobesity activity, including a reduction in food intake and body fat gain, an increase in fat, i.e., fatty acid oxidation, and a decrease in de novo lipogenesis (e.g., ref 64). Crude G. cambogia extracts also displayed antidiabetic, anti-inflammatory, anticancer, anthelmintic, and hepatoprotective effects in vitro and in vivo.62 The reduction in food intake by G. cambogia could partly be related to the stimulation of fatty acid oxidation, which has been proposed to have eating-inhibitory potential,65 or to the inhibition of serotonin re-uptake in serotonergic synapses in the brain that has been observed in response to hydroxycitric acid,66 a major component of G. cambogia extracts.67 Several studies with pure hydroxycitric acid, however, reported only weak effects of hydroxycitric acid on eating (e.g., ref 68), and the same holds for antiobesity studies performed with G. cambogia extracts (e.g., ref 69). Moreover, the possible toxicity associated with the regular use of G. cambogia extracts62,70 raises concerns. H. gordonii has traditionally been used by indigenous communities in the southern part of Africa to suppress hunger and thirst on long hunting trips.71 An increase in hypothalamic ATP and, hence, activation of a hypothalamic energy sensor72 and a stimulation of the secretion of the intestinal satiation peptide cholecystokinin (CCK)73 have been proposed as mechanisms of the eating-inhibitory effects of P57, which seems to be the major active compound responsible for the effects of H. gordonii. The unfavorable pharmacodynamics of P57 with a comparatively short biological half-life and a very limited bioavailability, however, raise critical questions about the dose of H. gordonii extracts that would have to be consumed to achieve a therapeutic or preventive effect. In fact, recent studies suggest a substantial interindividual variability with respect to absorption and bioavailability as well as severe adverse gastrointestinal effects when P57 is consumed in the high doses that are necessary for an eating-inhibitory effect. These adverse effects may actually contribute to the inhibition of eating because, even at lower doses consumed chronically, it seems to be difficult to dissociate the negative side effects from the inhibition of eating. All of this questions the usefulness of H. gordonii extracts as a weight control agent.63

progression of carcinogensis.51 Although these effects have also been shown in some human intervention trials, further investigations into the chemopreventive potential of HT and its related phenolic substances in olive oil are certainly warranted, in particular, intervention studies in people at high cancer risk.51 The evidence for several health beneficial effects, including the prevention of low-density lipoprotein (LDL) oxidative damage by HT, and, hence, for a reduction in the risk of cardiovascular disease was considered solid enough by the EFSA to approve the pertinent health claim for HT in 2011.52 This health claim suggests daily consumption of at least 5 mg of HT and its derivatives to reach these effects at the physiological level.17 With respect to obesity and metabolic syndrome, several findings implicate HT in the protective effect of virgin olive oil against high-fat-diet (HFD)-induced obesity, insulin resistance, dyslipidemia, hypertension, and associated complications (oxidative stress and inflammation).17,53,54 In laboratory animal models receiving HT supplementation with the diet, HT outperformed metformin, a standard therapeutic against T2D, with respect to its lowering effect on blood glucose and lipids as well as the oxidation levels of lipids and proteins in liver and muscle.53 Nevertheless, despite the EFSA approval and the solid evidence for potent pharmacological activities of HT in vitro and in vivo, the general consensus is that more in vivo studies with biologically relevant doses in humans are necessary to substantiate several of the health claims that are not fully documented.49 Unlike for several other polyphenols (e.g., resveratrol and curcumin), bioavailability does not appear to be a problem for HT because olive oil polyphenols are reasonably well-absorbed, in particular, in the olive oil matrix, and effective systemic and tissue concentrations are apparently reached.49,54 One aspect, however, that may hamper the widespread use of HT as a food supplement is its comparatively high price tag.55 Capsaicinoids and Capsaicin. Capsaicinoids are the pungent principle of hot peppers that have been used as pungent spices, in particular, in hot climates, but also in traditional medicine for centuries. Capsaicin (8-methyl-Nvanillyl-6-nonenamide) is the most common capsaicinoid. Although an anticancer effect56 and several other beneficial effects of capsaicin have been reported,57 the major healthpromoting effects of capsaicin appear to be related to its welldocumented effects on fat metabolism and eating; it increases energy expenditure, enhances lipolysis and fatty acid oxidation, and decreases food intake.16,58,59 As a result, capsaicin addition to a diet often causes weight loss, and perhaps even more important, it seems to be particularly effective in helping to maintain an achieved weight loss, which may be due to the fact that it counteracts the reduction of energy expenditure that usually accompanies weight loss. It is also important to note that all of these effects have been observed in humans under practically relevant conditions. Capsaicin exerts its actions through the transient receptor potential vanilloid receptor 1 (TRPV1).60 TRPV1 on sensory neurons in the oral cavity mediate the pungency of capsaicin. TRPV1 is a calcium channel that is ubiquitously expressed by sensory neurons and activated by different noxious stimuli. The activation of TRPV1 on sensory afferent neurons by capsaicin must stimulate sympathetic efferents because the thermogenic and body-fatlowering effects of capsaicin seem to be related to an activation of the sympathetic nervous system and subsequent increase in brown adipose tissue (BAT) thermogenesis.61 All in all, capsaicin may support weight management programs.

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THYLAKOIDS While the health beneficial effects of polyphenols have long been known, comparable effects of thylakoids were described fairly recently. Thylakoids are the chromophores of green plants, which surround the chlorophyll. Thylakoids contain about 100 different membrane proteins, some lipids, and various vitamins (A, E, and K) as well as antioxidants (carotinoids, lutein, etc.).74 Thylakoids appear to specifically D

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Figure 1. Schematic summary of the health beneficial effects of food components. Please see the text for further details. AMP kinase, adenosine monophosphate kinase; BAT, brown adipose tissue; CNS, central nervous system; eNOS, endothelial nitric oxide synthase; GSH, glutathione; NFκB, nuclear factor κB; and ROS, reactive oxygen species.

promoting PV-immunoreactive and/or γ-aminobutyric acidergic (GABAergic) neuronal activity.81 Finally, with respect to energy homeostasis, it is interesting to note that, in recent studies in humans, daily dashi ingestion increased gastrointestinal myoelectric activity, slowed gastric emptying, reduced hunger, and increased satiety sensations (T. Kondoh, unpublished observation). In short, several lines of evidence indicate that dashi somehow exerts beneficial effects on health, which may contribute to the longevity of Japanese people (http://www.agewatch.org.uk/secrets-of-longevity/japaneselongevity/).

and efficiently inhibit eating in humans and animals.74−76 This effect appears to be related to a stimulation of the secretion of satiating gut peptides, such as CCK and glucagon-like peptide 1 (GLP-1)74,75 and, possibly, to a stimulation of the oxidation of dietary-derived fatty acids in the small intestine.76 Interestingly, in humans, thylakoids appear to have a particularly strong inhibitory effect on hedonic eating, i.e., on the overeating when exposed to good-tasting, attractive food.75 The underlying mechanisms are still unclear. If thylakoids somehow also stimulate the release of central nervous system GLP-1 (in addition to their stimulatory effect on peripheral GLP-1), it could partly be related to the inhibition of hedonic eating because activation of GLP-1 receptors in the brain has been shown to reduce the rewarding effect of food.77

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SYNOPSIS All in all, it appears to be safe to say that many of the healthpromoting and disease-preventive effects of the aforementioned food components are presumably due to the effects of these substances on eating, metabolism (in particular, insulin sensitivity), and body weight/obesity. These effects are welldocumented in cell culture studies as well as in in vivo studies in laboratory animals and, partly, in humans. Furthermore, the beneficial effects reported for these substances are presumably related to one or more of the following mechanisms:14,16,62 (1) a reduction in food intake, (2) an inhibition of lipogenesis and an enhancement of lipolysis, (3) a stimulation of fatty acid oxidation, possibly primarily in small intestinal epithelial cells,65 (4) an inhibition of adipocyte differentiation (Figure 1), (5) an anti-inflammatory and antioxidative action, and (6) a regulation of gene expression (by epigenetic and other mechanisms). In addition, EGCG, perhaps P57, and certainly thylakoids also appear to stimulate the release of the satiating gut peptide CCK, and at least thylakoids stimulate the release of the

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DASHI The traditional Japanese stock “dashi” is an essential component of the Japanese cuisine.78 Its chronic/long-term consumption has been related to a number of positive health effects, such as an improved recovery from physical fatigue, a reduction of mental fatigue, an improved mental performance in a simple calculation task, and an improved mood and reduced anxiety status,79 to name but a few. Furthermore, dashi consumption reduced systolic blood pressure and urinary concentrations of stress markers.80 In a more recent study, the behavioral effects of dashi, such as decreased aggressiveness and depression-like symptoms, were reportedly related to increases in the densities of parvalbumin (PV)-immunoreactive neurons in the medial prefrontal cortex (mPFC), the amygdala, the hippocampus, and the superior colliculus.81 These results suggest that dashi might modulate emotional behaviors by E

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incretin and satiating gut peptide GLP-1. Very few substances may also have a direct effect on central nervous system circuitries that control eating and regulate energy homeostasis. Major open questions82 exist, however, with respect to (1) the translational relevance of results obtained in vitro or in laboratory experiments for human diseases (obviously, this is particularly relevant for all substances in which the bioavailability in humans is a major concern, such as for resveratrol, curcumin, and H. gordonii), (2) the extrapolation of effects observed in short-term studies, (3) the relevance of the employed/administered doses, in particular, when the generic substances were used instead of the pertinent food items, which does of course relate to the question of whether there are combinatorial effects of the compound in question with other food components, and (4) last but not least, the question of whether eventual effects have only preventive character or may also be useful for therapy. The evidence for health beneficial effects of food compounds should, therefore, be based on mechanistic, i.e., in vitro, and laboratory animal studies and clinical trials in humans. This is cumbersome, but given the importance of the steady increase in the incidence of non-communicable diseases for public health and the preventive and, in part, even therapeutic potential that some food components may have, further research into these questions is certainly warranted. It seems particularly important to elucidate their exact mechanisms of action and to find ways to recruit these effects in normal life situations. There are promising attempts to overcome at least some of these problems. Using metabolites of the compounds may be one option to overcome the problems of bioavailability and longer term action, provided that the metabolites retain biological activity. Peak plasma concentrations of resveratrol metabolites, (e.g., resveratrol-3-O-sulfate or resveratrol-3-O-glucuronide), for instance, were found to be much higher than for resveratrol, and these metabolites appear to retain some biological activity.83−85 In some tissues, sulfated metabolites of resveratrol may actually form intracellular stores that can release resveratrol over an extended time and, thus, regenerate its beneficial effects.86 Other promising approaches focus on special vehicles for absorption and transport, such as nanoparticles or nanoencapsulation87,88 or complex lipid formulations and rafts,89,90 which all appear to enhance bioavailability substantially. Thus far, these strategies focused primarily on resveratrol, but they may help to improve the pharmacodynamic profile of other compounds as well.

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*Telephone: +41-44-655-7420. Fax: +41-44-655-7206. E-mail: [email protected]. ORCID

Wolfgang Langhans: 0000-0001-9742-0068 Notes

The author declares no competing financial interest.

■

ACKNOWLEDGMENTS The author thanks Montse Argelagues-Feu (Innovation Division, Lucta, Montornes del Valles, Spain) for the stimulating and very helpful discussions. F

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