Chapter

Bioavailability and Metabolism of Ellagic Acid and Ellagitannins

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

Ellagitannins are hydrolyzable tannins that release ellagic acid upon hydrolysis. They exhibit various biological activities in vitro that have been associated with pharmacological (ellagitannin-containing medicinal plants) and nutritional (ellagitannin-containing foods) effects in vivo. The potential health effects are mainly related to the prevention of cardiovascular diseases and cancer. In vivo biological effects may be due partially to the potent free-radical scavenging activity that these compounds exert in vitro. It is, however, necessary to take into account the fate of ellagitannins in the gastrointestinal tract, their bioaccessibility, bioavailability, metabolism, and tissue distribution of the corresponding metabolites to understand the efcacy and the physiological role of dietary and medicinal ellagitannins. In the present chapter, we review the current knowledge regarding the bioavailability and metabolism of ellagitannins and point out various unresolved issues within these processes in humans that require further research.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... The health effects of many fruits, fruit juices, nuts, and seeds have been associated with their high content of antioxidant polyphenols and particularly in ellagitannins (ETs) able to provide ellagic acid (EA), one of the most powerful antioxidant molecules [1][2][3]. Food chemists consider both ETs and EA as nutraceuticals, because in addition to possessing the basic nutritional values, they are gifted with several extra health benefits, therefore the dietary intake of foods containing these components often translates in relevant biological effects. For example, documented findings assert a correlation among the consumption of ET-rich foods and greater cardiovascular health [1,[2][3][4] or among the consumption of fruits and vegetables and minor incidence of coronary heart disease [5]. ...
... Food chemists consider both ETs and EA as nutraceuticals, because in addition to possessing the basic nutritional values, they are gifted with several extra health benefits, therefore the dietary intake of foods containing these components often translates in relevant biological effects. For example, documented findings assert a correlation among the consumption of ET-rich foods and greater cardiovascular health [1,[2][3][4] or among the consumption of fruits and vegetables and minor incidence of coronary heart disease [5]. Moreover, much empirical data led to the hypothesis that both EA and ETs might be exploited to prevent chronic and degenerative diseases such as cancer, diabetes, cardiovascular diseases, and central nervous system (CNS) disorders [6]. ...
... The metabolism, which transforms EA in UROs, does not occur in all living species, due to the incapability to perform such metabolic pathway characterizing the microbiota of some species. Regardless, the UROs production from ETs has been reported for different animals (Table 11). 1 Young oak leaves 1 A, Iso A, B Pig (Sus scrofa domesticus) 1 Acorns 1 A, C, D, B Humans (Homo Sapiens) 1 Pomegranate juice 1 A, C, Iso A, B Humans (Homo Sapiens) 1 Pomegranate extract 1 A, B, C Humans (Homo Sapiens) 1 Walnuts 1 A, B, C Humans (Homo Sapiens) 1 Strawberry 1 A, C, Iso A, B Humans (Homo Sapiens) 1 Raspberry 1 A, C, Iso A, B Humans (Homo Sapiens) 2 Blackberry 2 A, C 2 Humans (Homo Sapiens) 3 Cloudberry 3 A 3 Humans (Homo Sapiens) 1 Oak-aged red wine 1 A 1 Humans (Homo Sapiens) 1 Tea 1 A 1 Humans (Homo Sapiens) 1 Nuts 1 A, Iso A, B 1 1 [38]; 2 [146]; 3 [44]. ...
Article
Full-text available
Oxidative stress (OS), triggered by overproduction of reactive oxygen and nitrogen species, is the main mechanism responsible for several human diseases. The available one-target drugs often face such illnesses, by softening symptoms without eradicating the cause. Differently, natural polyphenols from fruits and vegetables possess multi-target abilities for counteracting OS, thus representing promising therapeutic alternatives and adjuvants. Although in several in vitro experiments, ellagitannins (ETs), ellagic acid (EA), and its metabolites urolithins (UROs) have shown similar great potential for the treatment of OS-mediated human diseases, only UROs have demonstrated in vivo the ability to reach tissues to a greater extent, thus appearing as the main molecules responsible for beneficial activities. Unfortunately, UROs production depends on individual metabotypes, and the consequent extreme variability limits their potentiality as novel therapeutics, as well as dietary assumption of EA, EA-enriched functional foods, and food supplements. This review focuses on the pathophysiology of OS; on EA and UROs chemical features and on the mechanisms of their antioxidant activity. A discussion on the clinical applicability of the debated UROs in place of EA and on the effectiveness of EA-enriched products is also included.
... Current knowledge is summarized below, highlighting the latest advances and findings relevant to strawberry EA. Details can be found in earlier reviews (Landete, 2011;Larrosa et al., 2012;Espín et al., 2013). Both ETs and free EA are present in EA-rich foods. ...
... ETs are generally not absorbed in the human gastrointestinal tract, but they release free EA in the stomach and small intestine. Absorption of free EA can occur in the stomach and, but less importantly, in the small intestine (Espín et al., 2007;Larrosa et al., 2012). No transporters have been identified to date. ...
... Several animal studies reported EA accumulation in some organs and tissues (e.g. oesophagus, small intestine, colon, liver, lung, and prostate) (Boukharta et al., 1992;Larrosa et al., 2012). In humans, there is little evidence of EA accumulation in organs or tissues, except in human intestinal Caco-2 cells in vitro (Whitley et al., 2003). ...
Article
Full-text available
Ellagic acid (EA) is one of the plant phenolics associated with human health benefits. It derives from ellagitannins found in some nuts, seeds, and fruits, especially berries. Strawberries are considered a functional food and nutraceutical source, mainly because of their high concentration of EA and its precursors. This review presents the current state of knowledge regarding EA, focusing on its content in strawberry plants, stability during processing and storage of strawberry-based foods, production methods, and relevance to human health. As alternatives to acid-solvent extraction, fermentation-enzymatic bioprocesses hold great promises for more eco-efficient production of EA from plant materials. Strawberry fruits are generally rich in EA, with large variations depending on cultivar, growth conditions and maturity at harvest. High EA contents are also reported in strawberry achenes and leaves, and in wild strawberries. Strawberry postharvest storage, processing and subsequent storage can influence EA content. EA low concentration in strawberry juice and wine can be increased by incorporating pre-treated achenes. Widespread recognition of strawberries as functional foods is substantiated by evidence of EA biological effects, including antioxidant, antiinflammatory, antidiabetic, cardioprotective, neuroprotective, and prebiotic effects. The health benefits attributed to EA-rich foods are thought to involve various protective mechanisms at the cellular level. Dietary EA is converted by the intestinal microbiota to urolithins, which are better absorbed than EA and may contribute significantly to the health effects attributed to EA-rich foods. Based on the evidence available, strawberry EA shows strong promises for functional, nutraceutical, and pharmaceutical applications. Future research should be directed at quantifying EA in different parts of the strawberry plant and in their byproducts; optimizing EA production from byproducts; understanding the biological actions of EA-derived metabolites in vivo, including the interactions between EA metabolites, other substances and food/biological matrices; characterizing the conditions and microorganisms involved in urolithin production; and developing delivery systems that enhance EA functionality and bioactivity. Food Quality and Safety, 1(4), 2017, 227–252.
... Current knowledge is summarized below, highlighting the latest advances and findings relevant to strawberry EA. Details can be found in earlier reviews (Landete, 2011;Larrosa et al., 2012;Espín et al., 2013). Both ETs and free EA are present in EA-rich foods. ...
... ETs are generally not absorbed in the human gastrointestinal tract, but they release free EA in the stomach and small intestine. Absorption of free EA can occur in the stomach and, but less importantly, in the small intestine (Espín et al., 2007;Larrosa et al., 2012). No transporters have been identified to date. ...
... Several animal studies reported EA accumulation in some organs and tissues (e.g. oesophagus, small intestine, colon, liver, lung, and prostate) (Boukharta et al., 1992;Larrosa et al., 2012). In humans, there is little evidence of EA accumulation in organs or tissues, except in human intestinal Caco-2 cells in vitro (Whitley et al., 2003). ...
Article
Full-text available
Ellagic acid (EA) is one of the plant phenolics associated with human health benefits. It derives from ellagitannins found in some nuts, seeds, and fruits, especially berries. Strawberries are considered a functional food and nutraceutical source, mainly because of their high concentration of EA and its precursors. This review presents the current state of knowledge regarding EA, focusing on its content in strawberry plants, stability during processing and storage of strawberry-based foods, production methods, and relevance to human health. As alternatives to acid-solvent extraction, fermentation-enzymatic bioprocesses hold great promises for more eco-efficient production of EA from plant materials. Strawberry fruits are generally rich in EA, with large variations depending on cultivar, growth conditions and maturity at harvest. High EA contents are also reported in strawberry achenes and leaves, and in wild strawberries. Strawberry postharvest storage, processing and subsequent storage can influence EA content. EA low concentration in strawberry juice and wine can be increased by incorporating pre-treated achenes. Widespread recognition of strawberries as functional foods is substantiated by evidence of EA biological effects, including antioxidant, antiinflammatory, antidiabetic, cardioprotective, neuroprotective, and prebiotic effects. The health benefits attributed to EA-rich foods are thought to involve various protective mechanisms at the cellular level. Dietary EA is converted by the intestinal microbiota to urolithins, which are better absorbed than EA and may contribute significantly to the health effects attributed to EA-rich foods. Based on the evidence available, strawberry EA shows strong promises for functional, nutraceutical, and pharmaceutical applications. Future research should be directed at quantifying EA in different parts of the strawberry plant and in their byproducts; optimizing EA production from byproducts; understanding the biological actions of EA-derived metabolites in vivo, including the interactions between EA metabolites, other substances and food/biological matrices; characterizing the conditions and microorganisms involved in urolithin production; and developing delivery systems that enhance EA functionality and bioactivity.
... The health effects of pomegranate and pomegranate juice have been associated withthe high content in antioxidant polyphenols [1] and particularly in ellagitannins (punicalagins). This is also the case for many other ellagitannincontaining fruits and nuts such as strawberry, raspberry, blackberry, walnuts, and muscadine grapes [2,3]. ...
... Since urolithins are ellagitannin-derived catabolites that can be absorbed and reach different tissues in the body, they have been suggested as the molecules potentially responsible for the biological effects observed as a consequence of the consumption of pomegranate or other ellagitannincontaining foods [3,7,9,11]. Here we review the state of the art in urolithin metabolites production by gut microbiota, their absorption, tissue distribution and pharmacokinetics, the cell and molecular mechanisms for their biological effects reported so far using different in vitro models, and the in vivo evidence in animals and humans. ...
... Ellagic acid conjugates have also been detected, and these include methyl ether and glucuronyl and sulphate conjugates. The most common metabolite found in urine and plasma is ellagic acid dimethyl ether glucuronide, which involves the methylation by COMT and then the glucuronidation by glucuronyl-transferase [3,7]. The peak plasma levels of urolithin A were 14-25 M depending on the volunteers. ...
... The latter findings suggested that oenothein B exerts neurotrophic/neuroprotective effects in the brain because the phosphorylated ERK2 (pERK2)/ERK2 ratio and phosphorylated CREB (pCREB)/CREB ratio in the hippocampus were both shown to be significantly elevated by synaptic transmission and learning/memory formation [13,14] and CREB is a transcription factor for some neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) [15]. We speculated that in the latter case [12], any metabolite(s) of oenothein B (for example, urolithins) function in the brain because oenothein B, a large hydrophilic molecule, may be unable to reach the brain as it is [16]. Therefore, we are now investigating the urinary and plasma metabolite(s) of oenothein B. ...
... pus were both shown to be significantly elevated by synaptic transmission and learning/memory formation [13,14] and CREB is a transcription factor for some neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) [15]. We speculated that in the latter case [12], any metabolite(s) of oenothein B (for example, urolithins) function in the brain because oenothein B, a large hydrophilic molecule, may be unable to reach the brain as it is [16]. Therefore, we are now investigating the urinary and plasma metabolite(s) of oenothein B. ...
Article
Full-text available
(1) Background: The findings of our recent in vivo study indicated that the oral administration of oenothein B, a unique macrocyclic ellagitannin, activated extracellular signal-regulated kinase (ERK) 2 and cAMP response element-binding protein (CREB) in the mouse brain. A large hydrophilic oenothein B is unable to reach the brain, suggesting that any metabolite(s) of oenothein B might function in the brain. (2) Results: The addition of oenothein B to the culture medium of rat cortical neurons induced the prompt and significant activation of ERK2 and CREB. (3) Conclusions: The activation of ERK2 and CREB is crucial for synaptic transmission and learning/memory formation in the brain. The present results suggest oenothein B exerts neuro-trophic/neuroprotective effects in the brain through the modulation of neuronal signaling pathways, if it reaches the brain.
... Coumarins were reported to exert a negative effect on bacterial infections by inducing macrophages (Bor, Aljaloud, Gyawali, & Ibrahim, 2016). Based upon the biological effects in terms of absorption and distribution to different parts of the body, urolithins are ellagitannin-based catabolites observed after the consumption of ellagitannin-containing foods or pomegranate (Tomás- Barberan, Espín, & García-Conesa, 2009). Studies carried out in vitro attributed to the numerous and diverse health effects of urolithins, from antimalarial properties, antiviral properties to quenchers of bacterial quorum sensing. ...
... Coumarins are reported to exert a negative effect on bacterial infections by inducing macrophages (Bor et al., 2016). The biological effects observed as a consequence of the consumption of pomegranate or other ellagitannin-containing foods suggest that urolithins are ellagitannin-derived catabolites that can be absorbed and reach different tissues in the body(Tomás- Barberan et al., 2009). ...
Article
Full-text available
Leishmaniasis is considered a tropical neglected disease, which is caused by an intra‐macrophagicparasite, Leishmania. It is endemic in 89 different countries. Autophagy‐related protein 8 (Ldatg8) is responsible for the transformation of parasites from promastigote to amastigote differentiation. Ldatg8 is one of the key drug targets of Leishmania donovani (L. donovani) responsible for the defense of parasites during stress conditions. Virtual screening of natural ligands library hadbeen performed against Ldatg8 to identify novel and potent inhibitors. Molecular‐docking and molecular dynamics simulation studies showed that urolithin A stably blocked Ldatg8. Urolithins are combinations of coumarin and isocoumarin. Further, we evaluated the antileishmanial effects of urolithin A by antileishmanial assays. Urolithin A inhibited the growth and proliferation of L. donovani promastigotes with an IC50 value of 90.3 ± 6.014 μM. It also inhibited the intra‐macrophagic parasite significantly with an IC50 value of 78.67±4.62 μM. It showed limited cytotoxicity to the human THP‐1 differentiated macrophages with a CC50 value of 190.80 ± 16.89 μM. Further, we assayed reactive oxygen species (ROS) generation and annexin V/PI staining upon Urolithin A treatment of parasites to have an insight into the mechanism of its action. It induced ROS significantly in a dose‐dependent manner which caused apoptosis partially in parasites. The potential inhibitors for Ldatg8, identified in this study would provide the platform for the development of an effective and affordable antileishmanial drug. Urolithin A blocks autophagy‐related protein 8 and inhibits growth and proliferation of L. donovani
... Therefore, hydrophilic oenothein B may not have been able to pass through the BBB under the present experimental conditions. Previous studies showed that ellagitannins are generally transformed in the gut to ellagic acid (2,3,7,8-tetrahydroxy-benzopyrano [5,4,3-cde] benzopyran-5-10-dione), which is then converted to metabolites, such as urolithins (i.e., urolithin A, 3,8-dihydroxyurolithin and urolithin B, 3hydroxyurolithin), by gut bacteria [16][17][18]. We speculated that any metabolites penetrate and exert their effects in the brain. ...
... Therefore, hydrophilic oenothein B may not have been able to pass through the BBB under the present experimental conditions. Previous studies showed that ellagitannins are generally transformed in the gut to ellagic acid (2,3,7,8-tetrahydroxy-benzopyrano [5,4,3-cde] benzopyran-5-10-dione), which is then converted to metabolites, such as urolithins (i.e., urolithin A, 3,8-dihydroxyurolithin and urolithin B, 3-hydroxyurolithin), by gut bacteria [16][17][18]. We speculated that any metabolites penetrate and exert their effects in the brain. ...
Article
Full-text available
(1) Background: Oenothein B, a cyclic dimeric ellagitannin present in various medicinal plants, has been reported to exert diverse effects that are beneficial for the treatment and prevention of diseases, including cancer and infections. We recently showed that oenothein B also functions in the brain because its oral administration to systemic inflammatory model mice reduced inflammatory responses in the brain and suppressed abnormal behavior. (2) Results: The present in vivo results demonstrated that oenothein B activated extracellular signal-regulated kinase 2 and cAMP response element-binding protein in the brain, both of which play important roles in synaptic transmission and learning/memory in the central nervous system (CNS). (3) Conclusions: These results suggest that oenothein B exerts neuroprotective effects on the CNS by not only its anti-inflammatory activity but also by enhancing neuronal signaling pathways.
... The concentration of total EA ranged from 47 to 90 mg/g in red raspberries and black raspberries, respectively. The consumption of EA can exceed the above estimations if EA-rich foods other than berries (e.g., pomegranate juice and walnuts) are also present in the regular diet or if EA is taken as a supplement (45). In honey, EA has been suggested to be a floral marker for honey production from the heather plant (46). ...
... Upon hydrolysis, these compounds produce EA ( Figure 2); however, several other metabolites can also be produced that are discrete from individual ETs (i.e., gallagic and tergallagic acid-O-glucoside) (49,50). A survey performed in different geographical regions throughout the world suggested that citizens of Western Europe have the highest predictable daily dietary consumption of EA in both sexes (7.6 mg/d in men and 7.9 mg/d in women), followed by Americans and Australians (6.7 mg/d in women, 7.0 mg/d in men) (45,51). In these regions strawberries accounted for >60% of the daily intake of EA. ...
Article
Full-text available
Ellagic acid (EA) is a dietary polyphenol present in various fruits, vegetables, herbs, and nuts. It exists either independently or as part of complex structures, such as ellagitannins, which release EA and several other metabolites including urolithins following absorption. During the past few decades, EA has drawn considerable attention because of its vast range of biological activities as well as its numerous molecular targets. Several studies have reported that the oxidative stress–lowering potential of EA accounts for its broad-spectrum pharmacological attributes. At the biochemical level, several mechanisms have also been associated with its therapeutic action, including its efficacy in normalizing lipid metabolism and lipidemic profile, regulating proinflammatory mediators, such as IL-6, IL-1β, and TNF-α, upregulating nuclear factor erythroid 2-related factor 2 and inhibiting NF-κB action. EA exerts appreciable neuroprotective activity by its free radical–scavenging action, iron chelation, initiation of several cell signaling pathways, and alleviation of mitochondrial dysfunction. Numerous in vivo studies have also explored the neuroprotective attribute of EA against various neurotoxins in animal models. Despite the increasing number of publications with experimental evidence, a critical analysis of available literature to understand the full neuroprotective potential of EA has not been performed. The present review provides up-to-date, comprehensive, and critical information regarding the natural sources of EA, its bioavailability, metabolism, neuroprotective activities, and underlying mechanisms of action in order to encourage further studies to define the clinical usefulness of EA for the management of neurological disorders.
... Urolithins have a higher bioavailability and it is debatable whether urolithins formed in vivo are the main reason for the effects attributed to the ETs [106]. Given this background, it should be considered that cultured cells representing systemic tissues and organs may not be in direct contact in vivo with food ETs or EA [108]. In fact, it can be the cause of discrepancies between in vitro and in vivo results, which can also be linked to the inter-individual variability in quality and quantity of urolithin production [109]. ...
... it should be considered that cultured cells representing systemic tissues and organs may not be in direct contact in vivo with food ETs or EA [108]. In fact, it can be the cause of discrepancies between in vitro and in vivo results, which can also be linked to the inter-individual variability in quality and quantity of urolithin production [109]. ...
Article
Full-text available
Ellagitannins (ETs), characterized by their diversity and chemical complexity, belong to the class of hydrolysable tannins that, via hydrolysis under acidic or alkaline conditions, can yield ellagic acid (EA). They are mostly found as a part of extractives in angiosperms. As known antioxidants and chelators, EA and EA derivatives are drawing an increasing interest towards extensive technical and biomedical applications. The latter ones include possible antibacterial, antifungal, antiviral, anti-inflammatory, hepato- and cardioprotective, chemopreventive, neuroprotective, anti-diabetic, gastroprotective, antihyperlipidemic, and antidepressant-like activities, among others. EA’s synthesis and production challenges prompt further research on new methods and alternative sources. Conventional and prospective methods and raw materials for the production of EA and its derivatives are reviewed. Among the potential sources of EA, the residues and industrial streams of the pulp industry have been highlighted and considered as an alluring alternative in terms of commercial exploitation.
... 3,4 However, the majority of polyphenols, including the subclass known as ellagitannins, are poorly absorbed in the small intestine and do not achieve physiologically relevant concentrations in circulation. 5,6 Instead, they reach the colon where they are extensively metabolized by gut microbiota to colonic-derived metabolites, which are implicated with a vast array of biological effects. 7,8 Given considerable interindividual variability in microflora, and different phenotypes being observed with "metabolite-producers and nonproducers" after consumption of many polyphenol subclasses, including ellagitannins, 9 further investigations into understanding the biological effects of these colonic metabolites are necessary. ...
... The bioavailability and metabolism of ellagitannins in human subjects, after the consumption of pomegranate juice and pomegranate extracts, are well established. 5,6 The major pomegranate ellagitannins, PA and others, are not found intact ...
Article
Pomegranate shows neuroprotective effects against Alzheimer's disease (AD) in several reported animal studies. However, whether its constituent ellagitannins, and/or their physiologically relevant gut microbiota-derived metabolites, namely, urolithins (6H-dibenzo[b,d]pyran-6-one derivatives), are the responsible bioactive constituents is unknown. Therefore, from a pomegranate extract (PE), previously reported by our group to have anti-AD effects in vivo, twenty-one constituents, which were primarily ellagitannins, were isolated and identified (by HPLC, NMR and HRESIMS). In silico computational studies, used to predict blood brain barrier permeability, revealed that none of the PE constituents, but the urolithins, fulfilled criteria required for penetration. Urolithins prevented β-amyloid fibrillation in vitro and methyl-urolithin B (8-methoxy-6H-dibenzo[b,d]pyran-6-one), but not PE or its predominant ellagitannins, had a protective effect in Caenorhabditis elegans post induction of amyloid β1-42 induced neurotoxicity and paralysis. Therefore, urolithins are the possible brain absorbable compounds which contribute to pomegranate's anti-AD effects warranting further in vivo studies on these compounds.
... Ellagic acid (EA) and hydrolysable ellagitannins (ETs) are dietary polyphenols found in numerous fruits, vegetables and nuts such as pomegranate, blackberry, raspberry, chestnut, and walnut [1,2]. In the gut, ETs are easily hydrolyzed to release EA units through the in vivo action of physiological pH and/or the enzymatic activity of gut microflora [3]. ...
... In the gut, ETs are easily hydrolyzed to release EA units through the in vivo action of physiological pH and/or the enzymatic activity of gut microflora [3]. EA is known to possess many health benefits such as antioxidant, anticancer, antiatherosclerotic and other biological properties [1][2][3]. Therefore, elucidating the pharmacokinetic and tissue distribution profiles of EA is important, which can increase our understanding of the health beneficial mechanisms and provide more information for the scientific consumption of EA or EA/ETs-rich foods. The first study on the metabolism of EA was performed in rats after oral administration, and the concentrations of EA and its metabolites in urine and feces were reported [4]. ...
Article
Full-text available
Ellagic acid is a dietary polyphenol found in numerous fruits and vegetables, possessing several health benefits such as antioxidant, anticancer and anti-atherosclerotic biological properties. The purpose of this study was to explore the pharmacokinetics and tissue distribution of ellagic acid in rats. A simple, rapid, sensitive and specific liquid chromatography-tandem mass spectrometry method to determine the ellagic acid in plasma and tissue samples was developed and validated. The separation was achieved using reversed-phase ultra-performance liquid chromatography (UPLC), and the mass spectrometric detection was achieved using heated electrospray ionization (negative mode) and multiple ion monitoring (m/z 301/229). A sample cleanup with a solid phase extraction (SPE) step prior to the UPLC-MS/MS analysis was also developed. The SPE and UPLC-MS/MS method established here was successfully applied to reveal the pharmacokinetic profiles and tissue distribution of ellagic acid. After oral administration dosing at 50 mg/kg, plasma levels of ellagic acid peaked at about 0.5 h, with Cmax value of 93.6 ng/mL, and the results showed that the ellagic acid was poorly absorbed after oral administration. The pharmacokinetic profile of ellagic acid fitted to a two-compartment model with t1/2α 0.25 h and t1/2β 6.86 h, respectively. Following oral administration, ellagic acid was detected in all examined tissues including kidney, liver, heart, lung and brain et al., and the highest levels were found in kidney and liver.
... One glass of pomegranate juice (237 mL) can yield up to 300 mg of ellagitannins or about 120 mg of EA [138]. Around 100 g of raspberries produces 300 mg of ellagitannins and one strawberry yield up to 70 mg of ellagitannins [139]. However, urolithins have a greater absorption value than EA, possessing a higher lipo-solubility than free EA and, therefore, are more readily absorbed [17,140,141]. ...
Article
Full-text available
Obesity is in epidemic proportions in many parts of the world, contributing to increasing rates of non-alcoholic fatty liver disease (NAFLD). NAFLD represents a range of conditions from the initial stage of fatty liver to non-alcoholic steatohepatitis (NASH), which can progress to severe fibrosis, through to hepatocellular carcinoma. There currently exists no treatment for the long-term management of NAFLD/NASH, however, dietary interventions have been investigated for the treatment of NASH, including several polyphenolic compounds. Ellagic acid is one such polyphenolic compound. Nutraceutical food abundant in ellagic acid undergoes initial hydrolysis to free ellagic acid within the stomach and small intestine. The proposed mechanism of action of ellagic acid extends beyond its initial therapeutic potential, as it is further broken down by the gut microbiome into urolithin. Both ellagic acid and urolithin have been found to alleviate oxidative stress, inflammation, and fibrosis, which are associated with NAFLD/NASH. While progress has been made in understanding the pharmacological and biological activity of ellagic acid and its involvement in NAFLD/NASH, it has yet to be fully elucidated. Thus, the aim of this review is to summarise the currently available literature elucidating the therapeutic potential of ellagic acid and its microbial-derived metabolite urolithin in NAFLD/NASH.
... Enzymes in this environment are unable to decompose or hydrolyze them into ellagic acid units. As hydrolyzable tannins, their absorption initiates in the small intestine, primarily in the jejunum, following hydrolysis to ellagic acid [95]. In this study, the bioaccessibility of ellagic acid in blackberry leaves increased from 11.01% in the oral phase to 78.43% in the intestinal phase, while for raspberry leaves, a 6.46% bioaccessibility index was noted in the oral phase and increased to 35.46% in the intestinal phase. ...
Article
Full-text available
The goal of this research was nutritional evaluation through the phytochemical analysis of blackberry and raspberry leaves, the screening of their biological activity (antioxidant capacity and inhibition of lipid peroxidation), and the investigation of the effect of in vitro gastrointestinal digestion (GID) of blackberry and raspberry leaves on the bioaccessibility of polyphenol subclasses. The concentrations of the analyzed liposoluble antioxidants were higher (p < 0.05) in blackberry leaves compared to raspberry leaves, while a significant (p < 0.05) higher content of water-soluble antioxidants was registered in raspberry leaves (with a total polyphenol content of 26.2 mg GAE/g DW of which flavonoids accounted for 10.6 mg/g DW). Blackberry leaves had the highest antioxidant capacity inhibition of the superoxide radicals (O2•−), while raspberry leaves registered the highest inhibition of hydroxyl radicals (•OH), suggesting a high biological potency in scavenging-free radicals under in vitro systems. The maximum inhibition percentage of lipid peroxidation was obtained for blackberry leaves (24.86% compared to 4.37% in raspberry leaves), suggesting its potential to limit oxidative reactions. Simulated in vitro digestion showed that hydroxybenzoic acids registered the highest bioaccessibility index in the intestinal phase of both types of leaves, with gallic acid being one of the most bioaccessible phenolics. The outcomes of this investigation reveal that the most significant release of phenolic compounds from blackberry and raspberry leaves occurs either during or after the gastric phase. Knowledge about the bioaccessibility and stability of polyphenol compounds during digestion can provide significant insights into the bioavailability of these molecules and the possible effectiveness of plant metabolites for human health.
... Gallotannins are hydrolyzable tannins that contain gallic acid substituents [19]. When hydrolyzed by acids and under physiological conditions in the gastrointestinal tract, these gallotannins may release gallic acid [20]. Most studies report the role of condensed tannins related to anthelmintic activity. ...
Preprint
Full-text available
Objective: The usual control for gastrointestinal parasites is the use of commercial anthelmintics. However, parasites are becoming more resistant due to the frequent and inappropriate use of these anthelmintics. As a result, alternatives for these anthelmintics are becoming increasingly widespread for deworming livestock, particularly those that come from natural sources. Thus, this study aimed to evaluate the efficacy of mango seed extract in reducing the egg per gram counts of common gastrointestinal nematodes in pigs and compare the efficacy with that of levamisole. Results: Naturally-infected pigs served as experimental animals and were given a single dose of the mango seed extract at concentrations of 600, 700, and 800 mg per kg bodyweight. The extracts, regardless of concentration, was able to decrease the epg counts. Within 14 days post-treatment, there was no significant difference in the efficacies in the administration of 800 mg extract per kg bodyweight and levamisole. This comparable efficacies was sustained until 28 days post-treatment. This significant in vivo anthelmintic activity may be attributed to the tannins and flavonoids present in the extract. These results indicate that the mango seed extract is effective in controlling and reducing the gastrointestinal nematodes in pigs and may have the potential to be further developed as an anthelmintic.
... These results are in agreement with studies that identified these metabolites in the urine and plasma of rats that received 4% (w/w) of Myrciaria jaboticaba berry peel (MJP) for 10 weeks [13] and in humans that received an acute dose of JPSP (20 g/day) [37]. These metabolites are formed upon the absorption of ellagic acid in the initial portion of the small intestine, metabolized by catechol-O-methyl transferase, and conjugated with glucuronic acid [38], indicating enterohepatic circulation. ...
Article
Full-text available
The consumption of a high-fat diet can cause metabolic syndrome and induces host gut microbial dysbiosis and non-alcoholic fatty liver disease (NAFLD). We evaluated the effect of polyphenol-rich jaboticaba peel and seed powder (JPSP) on the gut microbial community composition and liver health in a mouse model of NAFLD. Three-month-old C57BL/6 J male mice, received either a control (C, 10% of lipids as energy, n = 16) or high-fat (HF, 50% of lipids as energy, n = 64) diet for nine weeks. The HF mice were randomly subdivided into four groups (n = 16 in each group), three of which (HF-J5, HF-J10, and HF-J15) were supplemented with dietary JPSP for four weeks (5%, 10%, and 15%, respectively). In addition to attenuating weight gain, JPSP consumption improved dyslipidemia and insulin resistance. In a dose-dependent manner, JPSP consumption ameliorated the expression of hepatic lipogenesis genes (AMPK, SREBP-1, HGMCoA, and ABCG8). The effects on the microbial community structure were determined in all JPSP-supplemented groups; however, the HF-J10 and HF-J15 diets led to a drastic depletion in the species of numerous bacterial families (Bifidobacteriaceae, Mogibacteriaceae, Christensenellaceae, Clostridiaceae, Dehalobacteriaceae, Peptococcaceae, Peptostreptococcaceae, and Ruminococcaceae) compared to the HF diet, some of which represented a reversal of increases associated with HF. The Lachnospiraceae and Enterobacteriaceae families and the Parabacteroides, Sutterella, Allobaculum, and Akkermansia genera were enriched more in the HF-J10 and HF-J15 groups than in the HF group. In conclusion, JPSP consumption improved obesity-related metabolic profiles and had a strong impact on the microbial community structure, thereby reversing NAFLD and decreasing its severity.
... Ellagitannins yield ellagic acid (monomeric unit) upon hydrolysis with acids or bases [6]. However, in vitro digestion studies have indicated that ellagitannins are in most cases considerably stable under the acidic conditions (pH 1.8-2.0) of the stomach, where the enzymes are incapable of decomposing or hydrolyzing them to ellagic acid units [116]. As they are hydrolyzable tannins, their absorption starts in the small intestine, mainly in the jejunum, after hydrolyzation to ellagic acid [117]. ...
Article
Full-text available
Berries have been widely assessed for their beneficial health effects, predominately due to their high (poly)phenol content of anthocyanins and ellagitannins. After ellagitannins and ellagic acid are metabolized by the gut microbiome, a class of compounds known as urolithins are produced, which exert potential advantageous health effects. Anthocyanins, on the other hand, undergo a complex metabolic pathway after their interaction with microbial and endogenous enzymes, forming a broad range of metabolites and catabolic products. In most cases, in vitro models and cell lines are used to generate metabolites, whereas their assessment in vivo is currently limited. Thus far, several analytical methods have been developed for the qualitative and quantitative analysis of phenolic metabolites in berries, including liquid chromatography, mass spectrometry, and other hyphenated techniques, and have been undoubtedly valuable tools for the detailed metabolite characterization and profiling. In this review, a compilation of studies providing information on the qualitative and quantitative analysis of (poly)phenol metabolites in blackberries and raspberries after the utilization of in vitro and in vivo methods is presented. The different analytical techniques employed are assessed, focusing on the fate of the produced metabolic compounds in order to provide evidence on their characteristics, formation, and beneficial effects.
... Thus, lignans after ingestion undergo directly bacterial hydrolysis and metabolism in the colon. Similarly, ellagitannins (ETs) are not readily absorbed but get hydrolysed into ellagic acid (EA) due to alkaline pH in the small intestine and the released ellagic acids undergo further bacterial metabolism in the colon (Tomás-Barberan et al., 2009). ...
Article
Phytoestrogens are a class of plant produced polyphenolic compounds with diphenolic structure, which is similar to 17β-estradiol. These phytoestrogens preferentially bind to estrogen receptors, however, with weak affinity. Recently, many studies have found that these phytoestrogens can be transformed by gut microbiota through novel enzymatic reactions into metabolites with altered bioactivity. Recent studies have also implied that these metabolites could possibly modulate the host gut ecosystem, gene expression, metabolism and the immune system. Thus, isolating gut microbes capable of biotransforming phytoestrogens and characterizing the novel enzymatic reactions involved are principal to understand the mechanisms of beneficial effects brought by gut microbiota and their metabolism on phytoestrogens, and to provide the theoretical knowledge for the development of functional probiotics. In the present review, we summarized works on gut microbial biotransformation of phytoestrogens, including daidzin (isoflavone), phenylnaringenin (prenylflavonoid), lignans, resveratrol (stilbene) and ellagitannins. We mainly focus on gut bacterial isolation, metabolic pathway characterization, and the bidirectional interaction of phytoestrogens with gut microbes to illustrate the novel metabolism capability of gut microbiota and the methods used in these studies.
... [7] In fact, these biotransformations are not limited to humankind, since other mammalian and non-mammalian species have been shown to possess this feature as well. [8] According to the metabolism studies, urolithin A (i.e., 3,8-dihydroxy-6H-benzo[c]chromen-6-one) and urolithin B (i.e., 3-hydroxy-6H-benzo[c]chromen-6-one) are the major metabolites formed. [9,10] Moreover, their methyl ether metabolites have also been shown to be produced via metabolism reactions. ...
Article
Urolithins (i.e., hydroxyl substituted benzo[c]chromen‐6‐one derivatives) are formed within the gastrointestinal tract following to the exposure to various ellagitannin rich diet, particularly involving pomegranate, nuts, and berries. Regarding the bioavailability deficiency of ellagitannins, the biological activities obtained through the extracts of these dietaries are attributed to the urolithin compounds, since they are bioavailable. Particularly, there are studies indicating the importance of ellagitannin rich food for protective and alternative treatment of Alzheimer’s Disease (AD). From this perspective, within this study, the major urolithins (i.e., Urolithin A and B), their methyl ether metabolites, as well as some synthetic urolithin analogues have been synthesized and screened for their biological activities in various enzyme inhibition (acetylcholinesterase, butyrylcholinesterase, monoamine oxidase B, cyclooxygenase 1, and cyclooxygenase 2) and antioxidant (DPPH radical scavenging) assay systems. The results, for the first time, pointed out the possible mechanisms of the activities of the urolithins for the treatment of AD with the corresponding structure activity relationships. Docking studies were also performed to investigate the possible interactions with the corresponding receptors.
... [7] In fact, these biotransformations are not limited to humankind, since other mammalian and non-mammalian species have been shown to possess this feature as well. [8] According to the metabolism studies, urolithin A (i.e., 3,8-dihydroxy-6H-benzo[c]chromen-6-one) and urolithin B (i.e., 3-hydroxy-6H-benzo[c]chromen-6-one) are the major metabolites formed. [9,10] Moreover, their methyl ether metabolites have also been shown to be produced via metabolism reactions. ...
Article
Full-text available
The detection and sensing of environmentally crucial metal ions has always been of great significance in various fields such as biological and environmental cycles. Our previous studies have indicated a new coumarin based lactone, Urolithin B (i.e., 3-Hydroxy[c]chromen-6-one) as a potent fluorescent probe for the selective detection of Iron (III). In order to question the extension of this application to other urolithins, we have synthesized the major urolithins that humans are exposed to through regular diet. Following the structure identifying studies, the compounds were tested in fluorescence titration to investigate their interaction with various metals. The results have indicated that each title compound is selective to interact with Iron (III) in ON-OFF mode, independent from the presence of another metal. Similar to the previous findings, the Job's plots displaying the ratio of complex formation 3:2 UROs:Fe3+ have indicated the significance of the lactone group solely.
... The placebo formulation (water, sucrose, and citric acid monohydrate, previously used in a study with healthy volunteers with no clinically relevant effects [28]) is designed to match the moisture (percentage), carbohydrate (percentage), total soluble solids content (degrees Brix), titratable acidity (percentage), and energy (kcal) of pomegranate juice. A daily dose of pomegranate juice provides an estimated 300 mg of ETs or higher [29]; ETs are absent in the placebo. ...
Article
Full-text available
Background: Inflammatory bowel disease (IBD) is a chronic condition characterized by recurrent episodes of intestinal inflammation and is thought to be related to an autoimmune reaction to genetic and environmental factors. Although evidence indicates that a polyphenolic-rich diet plays an important role in modulating aspects of chronic inflammation, few studies have focused on the effect of ellagitannin (ET)-rich food consumption on long-term remission maintenance in IBD patients with a high risk of clinical relapse. Therefore, we hypothesize that supplementation with a pomegranate juice, a naturally rich source of ETs, could significantly modulate the markers of mucosal and systemic inflammation relative to a control group receiving a placebo. Methods/design: This double-blind, randomized controlled trial includes patients with IBD involving the colorectum who have been in stable therapy for at least the three previous months and have a high risk of clinical relapse. Participants are randomly allocated to one of two groups: active supplementation (125 mL of cv. Wonderful pomegranate juice) or placebo (125 mL) taken twice daily for 12 weeks. The primary outcome is changes in the fecal neutrophil-derived protein calprotectin, a surrogate marker of mucosal improvement, between the two groups from baseline to 12 weeks later. The secondary outcomes include transcriptomic changes in peripheral blood mononuclear cells and intestinal biopsies and changes in circulating inflammatory markers and trimethylamine-N-oxide levels. Pomegranate ET-derived metabolites are identified and quantified in plasma and urine samples. Discussion: The results will provide information on the possible reduction of fecal calprotectin levels following the consumption of pomegranate juice. The findings will also show the in vivo metabolism of pomegranate ETs. Finally, the effect of 12-week pomegranate juice consumption on local and systemic inflammatory markers will be elucidated, which will likely provide additional insights into the maintenance of remission in IBD patients. Trial registration: ClinicalTrials.gov, NCT03000101 . Registered on 21 December 2016.
... Indeed, urolithins were detected in plasma of healthy humans 6 -8 h after intake of ellagitannin-rich pomegranate juice, suggesting that production occurs in the colon. The peak plasma levels of UroA in these volunteers were 14-25 µM [10][11][12][13]. In addition, high micromolar concentrations of urolithins have been found in the colon lumen of colorectal cancer patients [9] and feces of healthy suggests [35] consuming ETs-rich pomegranate extract. ...
Article
Full-text available
Urolithins (e.g., UroA and B) are gut microbiota-derived metabolites of the natural polyphenol ellagic acid. Urolithins are associated with various health benefits, including attenuation of inflammatory signaling, anti-cancer effects and repression of lipid accumulation. The molecular mechanisms underlying the beneficial effects of urolithins remain unclear. We hypothesize that some of the human health benefits of urolithins are mediated through the aryl hydrocarbon receptor (AHR). Utilizing a cell-based reporter system, we tested urolithins for the capacity to modulate AHR activity. Cytochrome P450 1A1 (CYP1A1) mRNA levels were assessed by real-time quantitative polymerase chain reaction. Competitive ligand binding assays were performed to determine whether UroA is a direct ligand for the AHR. Subcellular AHR protein levels were examined utilizing immunoblotting analysis. AHR expression was repressed in Caco-2 cells by siRNA transfection to investigate AHR-dependency. UroA and B were able to antagonize 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced AHR-mediated transcriptional activity. Furthermore, UroA and B attenuated TCDD-mediated stimulation of CYP1A1 mRNA levels. In addition, competitive ligand binding assays characterized UroA as a direct AHR ligand. Consistent with other AHR antagonists, UroA failed to induce AHR retention in the nucleus. AHR is necessary for UroA-mediated attenuation of cytokine-induced interleukin 6 (IL6) and prostaglandin-endoperoxide synthase 2 (PTGS2) expression in Caco-2 cells. Here we identified UroA as the first dietary-derived human selective AHR antagonist produced by the gut microbiota through multi-step metabolism. Furthermore, previously reported anti-inflammatory activity of UroA may at least in part be mediated through AHR.
... Therefore, biological activities of tannins and related polyphenols found in in vitro and in vivo assays have to be interpreted with caution, as noted in many papers or reviews, for the necessity of further studies. Increased interest for the fate of ellagitannins in the gastrointestinal tract has thus prompted investigations on the bioavailability or actual metabolites of ellagitannins in detail [55][56][57]81,82,86], and these aspects were reviewed by Tomas-Barberan et al. [87] and Torronen [88]. On the other hand, an oral delivery device, which encapsulates oenothein B or other ellagitannins, was reported for their enhanced protection through the gastrointestinal tract [89]. ...
Article
Full-text available
In 1990, Okuda et al. reported the first isolation and characterization of oenothein B, a unique ellagitannin dimer with a macrocyclic structure, from the Oenothera erythrosepala leaves. Since then, a variety of macrocyclic analogs, including trimeric–heptameric oligomers have been isolated from various medicinal plants belonging to Onagraceae, Lythraceae, and Myrtaceae. Among notable in vitro and in vivo biological activities reported for oenothein B are antioxidant, anti-inflammatory, enzyme inhibitory, antitumor, antimicrobial, and immunomodulatory activities. Oenothein B and related oligomers, and/or plant extracts containing them have thus attracted increasing interest as promising targets for the development of chemopreventive agents of life-related diseases associated with oxygen stress in human health. In order to better understand the significance of this type of ellagitannin in medicinal plants, this review summarizes (1) the structural characteristics of oenothein B and related dimers; (2) the oxidative metabolites of oenothein B up to heptameric oligomers; (3) the distribution of oenotheins and other macrocyclic analogs in the plant kingdom; and (4) the pharmacological activities hitherto documented for oenothein B, including those recently found by our laboratory.
... EA has a strong anti-carcinogenic role [22,23], 1 3 with its metabolites also being medicinally important [24]. The detail of bioavailability of EA and ellagitannins and their metabolites have been reviewed [25,26]. It was found that metabolites of EA and ellagitannins were biologically more active. ...
Article
Full-text available
Oxidative stress is a biological condition produced by a variety of factors, causing several chronic diseases. Oxidative stress was, therefore, treated with natural antioxidants, such as ellagic acid (EA). EA has a major role in protecting against different diseases associated with oxidative stress. This review critically discussed the antioxidant role of EA in biological systems. The in vitro and in vivo studies have confirmed the protective role of EA in suppressing oxidative stress. The review also discussed the mechanism of EA in suppressing of oxidative stress, which showed that EA activates specific endogenous antioxidant enzymes and suppresses specific genes responsible for inflammation, diseases, or disturbance of biochemical systems. The amount of EA used and duration, which plays a significant role in the treatment of oxidative stress has been discussed. In conclusion, EA is a strong natural antioxidant, which possesses the suppressing power of oxidative stress in biological systems.
... Thus, ellagic acid could be employed as a chemical signal of the availability of hydrolysable tannins within plant foods as well as being a bio-marker of the bioavailability of dietary ellagitannin [32]. Free ellagic acid is changed into dimethylated ellagic acid glucuronide within the gastrointestinal tract, and it is subsequently metabolised through the microbiota in the colon into hydroxyl products of dibenzopyran-6H-6-one, encompassing the subsequent compounds: 3,8-dihydroxyglucuronide-6-Hdibenzo-β-D-pyran-6-one, its aglycone urolithin A, glucuronide of hydroxy-6H-dibenzo--β-D-pyran-6-one, its aglycone urolithin B and glucuronide of 3,8,10-trihydroxy-6Hdibenzo-β-D-pyran-6-one [69]. Fig. (3) demonstrates alterations stimulated in ellagitannins and ellagic acid through the gastrointestinal microbiota [70]. ...
Article
Full-text available
Four distinguished although overlying stages make up the methodical procedure of wound healing, which are hemostasis, inflammation, proliferation and remodelling. Multiple sclerosis (MS) comprises a persistent inflammatory infection of the central nervous system, and is related to demyelination, neurodegeneration, as well as susceptibility to oxidative pressure. Obesity signifies a swiftly developing danger to the wellbeing of populations in a rising number of nations. Usually called diabetes mellitus (DM) by medical practitioners, diabetes details a collection of metabolic diseases within which the individual has raised blood glucose, either due to an insufficiency of insulin generation, or the lack of suitable response by the body to insulin, or both. Conventionally, the pomegranate, as well as its flowers, leaves, fruit juice and tree bark, has been applied in the treatment of conditions including acidosis, haemorrhage, diarrhoea and microbial contagions. Extracts of pomegranate have been established to contain intense anti-inflammatory, antioxidant as well as antitumor features in vivo as well as ex vivo. Of late, beneficial consequences of decrease of fat have been illustrated employing the pomegranate as well as its extracts. Several of the favourable consequences are associated with the availability of anthocyanins, tannins, and considerably elevated amounts of antioxidants, as well as flavonoids and polyphenols. A summary of the endeavours applied to deal with the possible advantages of the pomegranate towards healing wounds, Alzheimer’s disease (AD), diabetes mellitus (DM) and obesity, as well as an appraisal of the efficiency of intervention through the pomegranate and its extracts is provided in this article.
... ETs (hydrolysable tannins) on their hydrolysis yield gallic acid and ellagic acid from the compounds carrying gallyol groups and HHDP groups, respectively [28]. In vitro digestion models declare ETs to remain stable under the normal physiological condition of the stomach [30]. However, ETs hydrolysis to free ellagic acid or their degradation may proceed in the small intestine at neutral to alkaline pH [31]. ...
Article
Full-text available
It is universally accepted that diets rich in fruit and vegetables lead to reduction in the risk of common forms of cancer and are useful in cancer prevention. Indeed edible vegetables and fruits contain a wide variety of phytochemicals with proven antioxidant, anti-carcinogenic, and chemopreventive activity; moreover, some of these phytochemicals also display direct antiproliferative activity towards tumor cells, with the additional advantage of high tolerability and low toxicity. The most important dietary phytochemicals are isothiocyanates, ellagitannins (ET), polyphenols, indoles, flavonoids, retinoids, tocopherols. Among this very wide panel of compounds, ET represent an important class of phytochemicals which are being increasingly investigated for their chemopreventive and anticancer activities. This article reviews the chemistry, the dietary sources, the pharmacokinetics, the evidence on chemopreventive efficacy and the anticancer activity of ET with regard to the most sensitive tumors, as well as the mechanisms underlying their clinically-valuable properties.
... It is well studied that the ETs are not susceptible to hydrolysis or degradation in the acidic gastric pH or by enzymes secreted in stomach or by bile salts (Haslam, 2009;Tomas Barberan et al., 2009). The pH ideal for hydrolysis of ETs ranges from 7.0 to 7.3; hence, it is hydrolysed in the small intestine (Larrosa et al., 2006). ...
Article
Hydrolysable tannins (HTs) are secondary metabolites from plants, which are roughly classified into gallotannins and ellagitannins having gallic acid and ellagic acid residues respectively attached to the hydroxyl group of glucose by ester linkage. The presence of hexahydroxydiphenoyl and nonahydroxyterphenoyl moieties is considered to render antimicrobial property to HTs. HTs also show considerable synergy with antibiotics. Nevertheless, they have low pharmacokinetic property. The present review presents the scope of HTs as future antimicrobial agent. Copyright © 2016 John Wiley & Sons, Ltd.
... Alpha-amylase has been known to be inhibited by ellagitannins in the purified extract (Marcia et al., 2010). Seventy milligrams of ellagitannins are served per glass of strawberry juice (Barberan et al., 2009). p0230 ...
Chapter
Metabolomics as first described in 1998 is the study of all low-molecular-mass compounds synthesized and modified by a living cell or organism. Metabolic profiling (metabolomics/metabonomics) is the measurement in biological systems of the complement of low-molecular-weight metabolites and their intermediates that reflects the dynamic response to genetic modification and physiological, pathophysiological, and developmental stimuli. It involves the application of the combination of fields like analytical biochemistry, informatics, bioinformatics, and statistics for measuring metabolic products of living systems. Nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS) are among the key techniques involved. So far, chemical complexity, dynamic range, metabolic heterogeneity, and ease of extraction represent the most significant challenges in the development of this metabolomics technology. Use of metabolomics can help design novel and dedicated strategies to direct "metabolism" to the improvement of plants and their products and ultimately improve the variety of crops produced. Currently, the world has two highly contrasting nutrition-related problems-overconsumption and undernourishment-that would also receive attention by focusing on synthesizing nutritious food products along with their better yield. There is a dire need to address all the possible strategies that can be employed using this emerging field of science in improving crops that would not only help with increasing food demand but also help improve the economy.
... Alpha-amylase has been known to be inhibited by ellagitannins in the purified extract (Marcia et al., 2010). Seventy milligrams of ellagitannins are served per glass of strawberry juice (Barberan et al., 2009). p0230 ...
Chapter
Full-text available
Metabolomics as first described in 1998 is the study of all low-molecular-mass compounds synthesized and modified by a living cell or organism. Metabolic profiling (metabolomics/metabonomics) is the measurement in biological systems of the complement of low-molecular-weight metabolites and their intermediates that reflects the dynamic response to genetic modification and physiological, pathophysiological, and developmental stimuli. It involves the application of the combination of fields like analytical biochemistry, informatics, bioinformatics, and statistics for measuring metabolic products of living systems. Nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS) are among the key techniques involved. So far, chemical complexity, dynamic range, metabolic heterogeneity, and ease of extraction represent the most significant challenges in the development of this metabolomics technology. Use of metabolomics can help design novel and dedicated strategies to direct “metabolism” to the improvement of plants and their products and ultimately improve the variety of crops produced. Currently, the world has two highly contrasting nutrition-related problems—overconsumption and undernourishment—that would also receive attention by focusing on synthesizing nutritious food products along with their better yield. There is a dire need to address all the possible strategies that can be employed using this emerging field of science in improving crops that would not only help with increasing food demand but also help improve the economy. Keywords metabolomics; nutrigenomics; metabolite profiling; metabolite fingerprinting
... Alpha-amylase has been known to be inhibited by ellagitannins in the purified extract (Marcia et al., 2010). Seventy milligrams of ellagitannins are served per glass of strawberry juice (Barberan et al., 2009). p0230 ...
Chapter
Full-text available
Metabolomics as first described in 1998 is the study of all low-molecular-mass compounds synthesized and modified by a living cell or organism. Metabolic profiling (metabolomics/metabonomics) is the measurement in biological systems of the complement of low-molecular-weight metabolites and their intermediates that reflects the dynamic response to genetic modification and physiological, pathophysiological, and developmental stimuli. It involves the application of the combination of fields like analytical biochemistry, informatics, bioinformatics, and statistics for measuring metabolic products of living systems. Nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS) are among the key techniques involved. So far, chemical complexity, dynamic range, metabolic heterogeneity, and ease of extraction represent the most significant challenges in the development of this metabolomics technology. Use of metabolomics can help design novel and dedicated strategies to direct “metabolism” to the improvement of plants and their products and ultimately improve the variety of crops produced. Currently, the world has two highly contrasting nutrition-related problems—overconsumption and undernourishment—that would also receive attention by focusing on synthesizing nutritious food products along with their better yield. There is a dire need to address all the possible strategies that can be employed using this emerging field of science in improving crops that would not only help with increasing food demand but also help improve the economy.
... This is well in line with the claimed potential effects raised by the metabolites produced by the microbiota action on nut polyphenols. 42,43 The pattern of TAC solubilized with the enzyme treatment from bean and spinach showed many similarities, although spinach has absolute values about 3 times higher than bean. In both foods, about 30% of the TAC measured by chemical extraction was obtained using alkaline hydrolysis. ...
Article
This study aimed at elucidating the influence of food matrix on the release of antioxidant activity from five plant foods (apple, spinach, walnut, red beans and whole wheat). To this purpose a protocol based on sequential enzymatic digestion was adopted. The total antioxidant capacity (TAC) of solubilized and insoluble material were measured at each steps. Results showed that the overall TAC obtained by enzyme treatments was usually higher than that obtained by chemical extraction-based methods. In apple most of the TAC was released upon water washing and after pepsin treatment while in spinach, beans, and whole wheat the TAC released by treatments with bacterial enzymes was prominent. Walnut had the highest TAC value which was mainly released after pancreatin treatment. Therefore the enzyme treatment is fundamental to estimate the overall potential TAC of foods having a high amount of polyphenols bound to dietary fiber or entrapped in the food matrix.
... Berries were the main ETs contributors in both studies. Recently, Tomas-Barberan, Espin, and Garcia-Conesa (2009) suggested that the intake of dietary ETs may be much higher than previously estimated, especially if some of these ET-rich foods (Table 1) are regularly consumed in the diet. ...
Article
Ellagitannins (ETs) and ellagic acid (EA) are polyphenols present in some fruits, nuts and seeds, such as pomegranates, black raspberries, raspberries, strawberries, walnuts and almonds. ETs are hydrolyzed to EA under physiological conditions in vivo and EA is then gradually metabolized by the intestinal microbiota to produce different types of urolithins. Epidemiological evidence indicates that intake of ET and EA-rich foods may be protective against certain chronic diseases, although in vitro results often do not coincide with the findings of in vivo studies. This could be explained by the low bioavailability of ETs and EA antioxidant and the fact that urolithins are not as potent antioxidants as ellagitannins. On the other hand, urolithins could display estrogenic and/or anti-estrogenic activity and tissue disposition studies reveal that urolithins are enriched in prostate, intestinal, and colon tissues in mouse, which could explain why urolithins inhibit prostate and colon cancer cell growth. Moreover, antiproliferative and apoptosis-inducing activities of EA and urolithins have been demonstrated by the inhibition of cancer cell growth. The present work reviews the source, dietary intake, metabolism, functions and effects of ETs, EA and their derivate metabolites. Moreover, prebiotic, antioxidant and anti-inflammatory effects are also discussed.
Article
Breast cancer is a multifaceted, heterogeneous disease that manifests in the mammary gland. According to the WHO, more than 2.3 million cases are diagnosed each year, making it the most common malignancy among adults. The primary treatment of tumors includes chemotherapy, surgical resection, and radiotherapy. Although chemotherapy plays an irreplaceable role in tumor treatment, the drugs used generally show poor bioavailability, instability, lack of targeting, and toxicity. The major challenge facing chemotherapy regimens against cancers includes dose-limiting side effects on healthy tissues. A published meta-analysis indicated that only 0.7 % of the drug reaches the target. Thus, developing new therapies for the treatment of cancer is the need of the hour. The advent of drug resistance has been one of the major challenges facing researchers. Over the years, extensive investigations in the fields of cancer biomedical research and nanotechnology have evolved. Nanomedicine drugs have become an excellent alternative for the treatment of breast cancer, including Doxil®, Abraxane®, and other products widely used clinically. This review highlights potential strategies for the treatment of breast cancer and includes clinical trials data on available therapies. The role of immunotherapies including monoclonal antibodies, and the status of cancer vaccines have also been addressed in this work.
Article
Full-text available
Traditional herbal drugs are widely used for the treatment of various diseases. Ellagic acid (EA) as an herbal polyphenol metabolite exists in many medicinal plants. EA has an important role against natural and chemical toxicities due to its antioxidant and anti-inflammatory properties. For this review, several search engines or databases such as PubMed, Scopus, the Web of Science, and Google Scholar were used, and the most relevant published papers till February 2022 were included. The protective effects of EA against natural and chemical compounds are mediated through molecular mechanisms including scavenging of free radicals, modulation of proinflammatory cytokine synthesis, and reduction of lipid peroxidation. These properties make EA a highly fascinating compound that may contribute to different aspects of health; whereas, more studies are needed, especially on the pharmacokinetic profile of EA. In this review, we selected articles that include the protective effect of EA against several synthetic and natural toxins such as aflatoxin, lipopolysaccharide, acrylamide, and rotenone.
Article
Background: Obesity is often associated with impaired sensitivity to the effects of insulin (insulin resistance) and dietary protein (anabolic resistance) and may exacerbate the age-related decline of skeletal muscle (sarcopenia). Myostatin is a protein that negatively regulates skeletal muscle growth but its inhibition in rodents also improves insulin sensitivity. In humans, myostatin appears to be upregulated by obesity and associated with insulin resistance, but observations are confounded by lifestyle factors and ageing. Aims: To delineate between the effects of obesity and ageing on myostatin expression in human skeletal muscle; to investigate the underlying causes of these effects; and to establish the functional significance and interconnectivity of modulating insulin sensitivity and myostatin expression in human skeletal muscle cells. Methods: In Chapter 3 a cross-sectional analysis of skeletal muscle gene expression was undertaken, in conjunction with correlation analyses between serum myostatin and descriptive characteristics, to isolate the effects of obesity and ageing per se on myostatin expression and abundance. In Chapters 4 and 5, in vitro and ex vivo techniques were employed using human primary myotubes to investigate the potential involvement of lipid-induced insulin and anabolic resistance and secretory cross-talk between subcutaneous adipose tissue and muscle, in the obesity-mediated upregulation of myostatin and the associated impairment of insulin and anabolic sensitivity. In Chapter 6, the novel polyphenol metabolite Urolithin A was applied to human myotubes and a model of adipocytes, to investigate its therapeutic potential to enhance insulin and anabolic sensitivity and to suppress myostatin expression. Results: In Chapter 3 it was revealed that muscle myostatin expression is uniquely upregulated by obesity with ageing, but not by ageing in the absence of obesity, and occurs concurrently with insulin resistance and abnormal regulation of pathways involved in the maintenance of skeletal muscle mass. This association was corroborated by positive correlations between serum myostatin and multiple indices of adiposity, but not age. In Chapters 4 and 5 it was demonstrated that neither acutely elevated fatty acid availability (which induced insulin and anabolic resistance), nor chronic exposure to obese subcutaneous adipose tissue conditioned medium (which did not induce insulin or anabolic resistance but altered the expression of genes involved in myogenesis and muscle protein breakdown) recapitulated the obesity-mediated upregulation of myostatin expression. In Chapter 6 it was demonstrated for the first time that Urolithin A suppresses myostatin expression and enhances glucose transport in human myotubes (and 3T3-L1 adipocytes), the latter of which was associated with an upregulation of GLUT4 expression. Conclusions: Skeletal muscle myostatin expression is uniquely upregulated by obesity per se, but this does not appear to be mediated by lipid-induced insulin resistance, nor by the secretory milieux of obese subcutaneous adipose tissue. Nevertheless, both models perturbed factors involved in myogenesis and muscle protein breakdown, independent of an upregulation of myostatin. Thus, the factors responsible for the obesity-mediated upregulation of myostatin remain to be elucidated and future work to establish such causality is required. Furthermore, translational research to investigate the potential of Urolithin A to enhance glucose handling in peripheral tissues and to repress myostatin’s inhibitory effects on muscle growth is warranted in humans and could be of particular benefit in conditions such as sarcopenic obesity.
Article
Ellagitannins, the main components of walnut kernel polyphenols, are easily degraded by heating to produce ellagic acid, precursor in the production of urolithins that show multiple physiological functions. To analyze the conversion of ellagitannins to free ellagic acid in walnut kernels during baking, a quantitative method was developed to investigate the ellagic acid content (EAC) in free phenolic acid (FPA), acid-hydrolyzable phenolic acid (AHPA), and bound phenolic acid (BPA) fractions. The results showed that the EAC in FPA reached its maximum (5.17 ± 0.30 mg/g DW) after baking at 165 °C for 30 min, which increased by 99.52% compared with the control. Meanwhile, the content of ellagitannins (ETC) in AHPA and BPA dropped by 89.14% and 26.08%, respectively. It suggested that baking promoted the conversion of ellagitannins in AHPA and BPA to ellagic acid in FPA. Eight ellagitannins were regarded as the main precursors of ellagic acid in walnut kernels.
Article
Full-text available
In the last few decades, the rate of the production of new antibiotic has declined significantly. This is mainly due to the high costs needed for both research and development processes. On the other hand, antibacterial resistance developed by bacteria against the already present antibiotics has been increasing extensively. Thus, finding alternatives to synthesize new antimicrobial molecules is now a priority to fight against resistant bacteria. One of these alternatives that can be used as precursors for new antimicrobial molecules is secondary metabolites. Ellagitannins, abundantly found in walnut, pomegranate, and berries, are known as precursors of ellagic acid which possess antimicrobial, anticancer, and antioxidant activities. Ellagic acid is metabolized in mammalian gastrointestinal system via gut microbiota to form dibenzo [b, d] pyran-6-one metabolites, which are known as urolithins. Urolithins are the metabolites of ellagic acid which are responsible for its biological activities. There are many types of urolithins such as urolithin A, urolithin B, urolithin C and urolithin D that were detected in mammalian gastrointestinal tract. Urolithins were shown to possess antimicrobial activity against bacteria, viruses and fungi. In this article, it was aimed to review the antimicrobial activities of various natural and synthetic urolithins concomitant to their chemistry.
Chapter
The human body is a battlefield involving the immune system, pathogenic invaders, and the body's own abnormalities at all times. The immune system constitutes a complex network of highly specialized cells, tissues, organs, and proteins that interoperate in multifaceted mechanisms to provide an exclusion barrier and homeostasis. A compromise or overreaction in this substantial harmony can lead to scathing aftermath, such as inflammatory, autoimmune, or immunodeficiency related diseases. On the other hand, nutrition may have a key role in immune competence. Several foods have demonstrated immunoregulatory capacities, including proinflammatory cytokine synthesis, immune cell regulation, and gene expression. These cellular and molecular immune responses have principally been ascribed to diverse secondary metabolites. However, most of the latter are considered as xenobiotics and are highly metabolized postingestion and hence reducing the bioavailability. Hence, before warranting immunomodulatory properties to particular food, its journey through the human gastrointestinal tract should be considered. This chapter, hence, provides an overview of the immunomodulatory properties of three food plants with a long human history Curcuma longa, Punica granatum, and Moringa oleifera and their bioactive compounds as well as their bioavailability profile.
Article
Human tumors comprise subpopulations of cells called cancer stem cells (CSCs) that possess stemness properties. CSCs can initiate tumors and cause recurrence, metastasis and are also responsible for chemo‐ and radio‐resistance. CSCs may use signaling pathways similar to normal stem cells, including Notch, JAK/STAT, Wnt and Hedgehog pathways. Ellagitannins (ETs) are a broad group of substances with chemopreventive and anticancer activities. The antitumor activity of ETs and their derivatives are mainly related to their antiinflammatory capacity. They are therefore able to modulate secretory growth factors and pro‐inflammatory mediators such as IL‐6, TGF‐β, TNF‐α, IL‐1β and IFN‐γ. Evidence suggests that ETs display their anticancer effect by targeting CSCs and disrupting stem cell signaling. However, there are still few studies in this field. Therefore, high‐quality studies are needed to firmly establish the clinical efficacy of the ETs on CSCs. This paper reviews the structures, sources and pharmacokinetics of ETs. It also focuses on the function of ETs and their effects on CSCs‐related cytokines and the relationship between ETs and signaling pathways in CSCs.
Article
Globally, one of the alarming problems is the prevalence and burden of liver diseases, which accounts for 2 million cases per year. Chronic liver aetiologies such as hepatitis infections, alcoholic or non‐alcoholic liver disease, environmental agents, and drug‐induced toxicity are invariably responsible for liver fibrosis progression to finally hepatocellular carcinoma. Current treatment options are unable to overwhelm and cure liver diseases. Emerging findings suggest researchers' interest in using evidence‐based complementary medicine such as ellagic acid with extensive pharmacological properties. They include antioxidant, anti‐inflammatory, anti‐hyperlipidaemic, anti‐viral, anti‐angiogenic, and anticancer activity. The molecular functions elicited by ellagic acid include scavenging of free radicals, regulation of lipid metabolism, the prohibition of fibrogenesis response‐mediating proteins, inhibits hepatic stellate cells and myofibroblasts, restrains hepatic viral replication, facilitates suppression of growth factors, regulates transcription factors, proinflammatory cytokines, augments the liver immune response, fosters apoptosis and inhibits cell proliferation in tumorigenic cells. This review will most notably focus on preclinical and clinical information based on currently available evidence to warrant ellagic acid's prospective role in preventing liver diseases.
Chapter
The hydrolyzable tannins ellagitannins (ETs) and ellagic acid (EA) are polyphenols present in food sources such as pomegranates, berries, and walnuts. However, they are poorly absorbed on consumption, but the gut microbiota metabolizes them. In recent decades, an extensive literature has attributed a wide range of beneficial effects to these natural compounds based on their biological activities, including antioxidant, chemopreventive, antiinflammatory, cardioprotective, etc. However, in the last decade, knowledge of their bioavailability and metabolism has prompted research into the physiological role of their in vivo metabolites generated by gut microbiota action, the urolithins, which have received recognition across the world as possible candidates for health benefits. This chapter summarizes the latest developments and knowledge on the occurrence, dietary intake, bioavailability and metabolism, and biological effects of ellagitannins and ellagic acid supplementation, paying particular attention to the activity of their gut microbiota‐derived metabolites – urolithins.
Chapter
Full-text available
Cancer is still a major public health burden because its incidence and mortality continue to increase worldwide. The limited treatment options for patients with advanced stages, the severe toxicity, the onset of multiple drug resistance and the high costs of current anticancer therapies favor poor prognosis and high mortality rates. Thus, the identification and development of preventive and cost effective therapeutic strategies to reverse cancer-associated morbidity and mortality are needed. Vegetable and fruit consumption is associated with decreased risk of cancer because of its chemopreventive and chemotherapeutic effects. The use of Punica granatum preparations has a long ethnomedical history and preclinical research has reported many pharmacological activities, including chemopreventive, chemosensitisation and chemotherapeutic effects. Many of these health beneficial effects are related to its complex chemical composition and synergistic interactions of its colonic microbial metabolites including ellagic acid, ellagitannins, punicic acid, flavonoids, anthocyanidins, anthocyanins, and estrogenic flavonols. This chapter summarizes the scientific evidence supporting anticancer effects of pomegranate constituents, focusing on its molecular targets and anticancer mechanisms of action, along with a critical evaluation of pomegranate polyphenols as future anticancer agents.
Article
Sirt3 enzyme and mitochondrial abnormality can be related to excess fatigue or muscular dysfunction in multiple sclerosis (MS).Ellagic acid (EA) has a mitochondrial protector, iron chelator, antioxidant, and axon regenerator in neurons.In this study the effect of EAon muscle dysfunction, its mitochondria, and Sirt3 enzyme incuprizone-induced model of MSwas examined. Demyelination was induced by a diet containing 0.2% w/w cuprizone (Cup) for 42 days and EA administered daily (5, 50, and 100 mg/kg P.O) either with or without cuprizone in mice. Behavioral tests were assessed, and muscle tissue markers ofoxidative stress, mitochondrial parameters, mitochondrial respiratory chain activity, the Sirt3 protein level, and Sirt3 expression were also determined. Luxol fast blue staining and the behavioral tests were performed toassess the implemented model. In Cup group an increased oxidative stress in their muscle tissues was observed. Also, muscle mitochondria exhibited mitochondria dysfunction, lowered mitochondrial respiratory chain activity, Sirt3 protein level, and Sirt3 expression.EA prevented most of these anomalous alterations. Sub-chronicEA co-treatment dose-dependently ameliorated behavioral and muscular impairment in mice that received Cup.EA can effectively protect muscle tissue against cuprizone-induced demeylination via the mitochondrial protection, oxidative stress prevention and Sirt3 overexpression.
Article
It is well-known that the health properties attributed to several fruits, herbs, seeds and their processed foods/beverages are due to an important group of natural polyphenols classified as hydrolysable tannins (HT) named ellagitannins (ETs), that encompass both one or more gallic acid (GA) units and one or more hexahydroxydiphenoic acid (HHDP) units, ester-connected with a sugar residue. In vivo, ETs are rather not absorbed and in gastrointestinal tract (GIT), they are hydrolysed providing mainly ellagic acid (EA). Due to its trivial water-solubility, first pass effect, metabolism in GIT, or irreversible binding to cellular DNA and proteins, EA has a very low bioavailability. Some authors are studying methods to increase EA water-solubility and thus to improve its bioavailability. At the same, EA metabolism to urolithins (UROs), whose concentration and activity is inter-individual and intra-individual dependent, is still under study and not completely elucidate. Numerous in vitro and in vivo studies have been carried out to define the molecular and cellular events underlying the beneficial effects that this compound and its metabolites exert in pathological conditions. The anti-inflammatory and the antioxidant properties of EA attracted the interest of researchers for its potential health benefits in humans, including anti-cancer, anti-diabetes activities and cardio-protection. Nevertheless, lately the attention paid to EA is focusing on its potential protective action towards several neurodegenerative disorders. Thus, EA is investigated as a potential "lead compound" endowed with multi-target pharmacological properties on CNS. Since the identification of the pharmacophore(s) responsible for both health benefits and collateral effects of this compound is crucial in drug discovery, this review aims to provide an all-round updated analysis of the literature concerning EA involvement in several CNS disorders, hoping that such information will be useful to researchers involved in multi-target drug design for CNS.
Article
Full-text available
The increasing popularity of “Mirto” liqueur, produced from Myrtus communis berries, has led to the planting of domesticated cultivars, expanding myrtle berry production. To promote the use of cultivated berries, the content in the nutraceutical compounds ellagitannins has been investigated both in spontaneous and cultivated fruits. Oenothein B and eugeniflorin D2, characterized by ¹H and ¹³C NMR, were isolated and quantified using ultrahigh-performance liquid chromatography–diode array detector–tandem mass spectrometry (UPLC–DAD–MS/MS). The antifungal and anti-inflammatory activities of oenothein B were assayed in vitro. Large amounts of oenothein B and eugeniflorin D2 were detected in seeds (12 ± 2.4 and 5.8 ± 1.2 mg/g). The oenothein B concentration in liqueurs was 194 ± 22 mg/L. This macrocyclic ellagitannin dimer showed anti-Candida (minimal inhibitory concentration <8–64 μg/mL) and anti-inflammatory properties. Cultivated myrtle berries are a source of nutraceutical compounds. The high concentration of oenothein B in liqueur suggests a possible contribution to the organoleptic and biological properties of the beverage.
Chapter
Ellagic acid (EA) is a polyphenolic compound with antiviral activity against chikungunya, a rapidly spreading new tropical disease transmitted to humans by mosquitoes and now affecting millions worldwide. The most common symptoms of chikungunya virus infection are fever and joint pain. Other manifestations of infection can include encephalitis and an arthritic joint swelling with pain that may persist for months or years after the initial infection. The disease has recently spread to the U.S.A., with locally-transmitted cases of chikungunya virus reported in Florida. There is no approved vaccine to prevent or medicine to treat chikungunya virus infections. In this study, the Estimated Daily Intake (EDI) of EA from the food supply established using the National Health and Nutrition Examination Survey (NHANES) is used to set a maximum dose of an EA formulation for a high priority clinical trial.
Article
Fünf Portionen Obst und Gemüse am Tag! Das ist nach heutigen Maßgaben nötig, um fit und gesund zu bleiben, das wird überall empfohlen und ebenso heftig beworben. Regelmäßig grüner Tee, ab und zu Schokolade sowie der Genuss von ein paar Gläschen Rotwein am Tag sollen zusätzlich lebensverlängernd wirken. Warum? Eine vollständige Antwort darauf kann die Wissenschaft noch nicht geben, aber eine bestimmte Klasse von natürlichen Substanzen, die in Obst und Gemüse vorkommt, gilt allgemein als besonders gesundheitsfördernd: die Polyphenole! Was aber sind diese pflanzlichen Stoffe genau? Welche physikalisch-chemischen Eigenschaften haben sie? Wie entfalten sie ihre biologische Wirkung? Können sie wirklich der Vorbeugung von Krankheiten dienen? Können aus ihnen neue Arzneimittel entwickelt werden? Wie weit ist die organische Synthese, um sie herzustellen? Dieser Aufsatz gibt einige Antwort aus der chemischen Perspektive, fasst den aktuellen Stand der Dinge zusammen und stellt die wichtigsten Fortschritte in der Polyphenolforschung vor.
Article
Recent research on the bioavailability of flavan-3-ols after ingestion of green tea by humans is reviewed. Glucuronide, sulfate, and methyl metabolites of (epi)catechin and (epi)gallocatechin glucuronide reach peak nanomolar per liter plasma concentrations 1.6-2.3 h after intake, indicating absorption in the small intestine. The concentrations then decline, and only trace amounts remain 8 h after ingestion. Urinary excretion of metabolites over a 24-h period after green tea consumption corresponded to 28.5% of the ingested (epi)catechin and 11.4% of (epi)gallocatechin, suggesting higher absorption than that of most other flavonoids. The fate of (-)-epicatechin-3-O-gallate, the main flavan-3-ol in green tea, is unclear because it appears unmetabolized in low concentrations in plasma but is not excreted in urine. Possible enterohepatic recirculation of flavan-3-ols is discussed along with the impact of dose and other food components on flavan-3-ol bioavailability. Approximately two-thirds of the ingested flavan-3-ols pass from the small to the large intestine where the action of the microbiota results in their conversion to C-6-C-5 phenylvalerolactones and phenylvaleric acids, which undergo side-chain shortening to produce C-6-C-1 phenolic and aromatic acids that enter the bloodstream and are excreted in urine in amounts equivalent to 36% of flavan-3-ol intake. Some of these colon-derived catabolites may have a role in vivo in the potential protective effects of tea consumption. Although black tea, which contains theaflavins and thearubigins, is widely consumed in the Western world, there is surprisingly little research on the absorption and metabolism of these compounds after ingestion and their potential impact on health.
Article
Full-text available
For some classes of dietary polyphenols, there are now sufficient intervention studies to indicate the type and magnitude of effects among humans in vivo, on the basis of short-term changes in biomarkers. Isoflavones (genistein and daidzein, found in soy) have significant effects on bone health among postmenopausal women, together with some weak hormonal effects. Monomeric catechins (found at especially high concentrations in tea) have effects on plasma antioxidant biomarkers and energy metabolism. Procyanidins (oligomeric catechins found at high concentrations in red wine, grapes, cocoa, cranberries, apples, and some supplements such as Pycnogenol) have pronounced effects on the vascular system, including but not limited to plasma antioxidant activity. Quercetin (the main representative of the flavonol class, found at high concentrations in onions, apples, red wine, broccoli, tea, and Ginkgo biloba) influences some carcinogenesis markers and has small effects on plasma antioxidant biomarkers in vivo, although some studies failed to find this effect. Compared with the effects of polyphenols in vitro, the effects in vivo, although significant, are more limited. The reasons for this are 1) lack of validated in vivo biomarkers, especially in the area of carcinogenesis; 2) lack of long-term studies; and 3) lack of understanding or consideration of bioavailability in the in vitro studies, which are subsequently used for the design of in vivo experiments. It is time to rethink the design of in vitro and in vivo studies, so that these issues are carefully considered. The length of human intervention studies should be increased, to more closely reflect the long-term dietary consumption of polyphenols.
Article
Full-text available
Six anthocyanin pigments were found to be responsible for the red colour of pomegranate juice (cv ‘Mollar’). These were analysed quantitatively and qualitatively by HPLC and identified as delphinidin 3-glucoside and 3,5-diglucoside, cyanidin 3-glucoside and 3,5-diglucoside and pelargonidin 3-glucoside and 3,5-diglucoside. The fruit skin contained only the cyanidin and pelargonidin derivatives. Generally, there is an increase in juice pigmentation with fruit ripening. During early maturation stages the 3,5-diglucosides were the main pigments and the delphinidin-based derivatives were the predominant compounds. In late maturation stages the proportion of monoglucosides increased to reach values similar to or higher than those of the diglucosides, and the cyanidin-based derivatives were the predominant substances. The concentration of pigments in juice obtained from mature pomegranates ranged between 50 and 100 μg of anthocyanin per gram fresh weight of arils. The development of anthocyanins was also tested in fruits produced in two different orchards, and in fruits from different locations in the tree. Red coloured fruits, located in the outer parts of the tree, and yellow fruits, on the inner branches, were analysed. The juices obtained with the seed coats of both fruit types, and from the two orchards selected, showed the same anthocyanin profile. However, the total amount of pigments in the juice was generally smaller in those fruits with reddish skins (outer fruits), than in those with yellow skins (inner fruits). As juice pigmentation is one important quality factor in pomegranate, these results could be used in on-line determinations of the pomegranate quality by non-destructive physical methods.
Article
Full-text available
Eurasian beavers (Castor fiber) live in family groups that defend territories against other conspecifics. Part of this territorial defence involves constructing scent mounds near the stream bank within territories and marking them with castoreum, a urine-based fluid from the castor sacs, and (or) anal-gland secretion. The aim of this study was to test the hypothesis that Eurasian beavers show one or more forms of territorial behavior when an intruder, simulated in the form of experimental scent mounds (ESMs), has scent-marked inside the territory. We predicted that beavers would show a stronger response to ESMs with castoreum than to those without. Results showed that 85% of all beaver families (N = 20) made one or more behavioral responses to ESMs marked with castoreum from foreign adult males, whereas no ESMs presented without castoreum received a response. We therefore conclude that a main function of territorial marking by beavers is to advertise spatially related dominance status, thereby providing opportunities for intruders to assess the presence of the owner and reducing the cost and risks of agonistic conflict for both the owner and intruders. Additionally, it appears to be the scent emitted from an ESM and not the sight of it to which beavers respond.
Article
Full-text available
Dietary supplementation with nutrients rich in antioxidants is associated with inhibition of atherogenic modifications to LDL, macrophage foam cell formation, and atherosclerosis. Pomegranates are a source of polyphenols and other antioxidants. We analyzed, in healthy male volunteers and in atherosclerotic apolipoprotein E-deficient (E(0)) mice, the effect of pomegranate juice consumption on lipoprotein oxidation, aggregation, and retention; macrophage atherogenicity; platelet aggregation; and atherosclerosis. Potent antioxidative effects of pomegranate juice against lipid peroxidation in whole plasma and in isolated lipoproteins (HDL and LDL) were assessed in humans and in E(0) mice after pomegranate juice consumption for </=2 and 14 wk, respectively. In humans, pomegranate juice consumption decreased LDL susceptibility to aggregation and retention and increased the activity of serum paraoxonase (an HDL-associated esterase that can protect against lipid peroxidation) by 20%. In E(0) mice, oxidation of LDL by peritoneal macrophages was reduced by up to 90% after pomegranate juice consumption and this effect was associated with reduced cellular lipid peroxidation and superoxide release. The uptake of oxidized LDL and native LDL by mouse peritoneal macrophages obtained after pomegranate juice administration was reduced by 20%. Finally, pomegranate juice supplementation of E(0) mice reduced the size of their atherosclerotic lesions by 44% and also the number of foam cells compared with control E(0) mice supplemented with water. Pomegranate juice had potent antiatherogenic effects in healthy humans and in atherosclerotic mice that may be attributable to its antioxidative properties.
Article
Full-text available
The antioxidant activity of pomegranate juices was evaluated by four different methods (ABTS, DPPH, DMPD, and FRAP) and compared to those of red wine and a green tea infusion. Commercial pomegranate juices showed an antioxidant activity (18-20 TEAC) three times higher than those of red wine and green tea (6-8 TEAC). The activity was higher in commercial juices extracted from whole pomegranates than in experimental juices obtained from the arils only (12-14 TEAC). HPLC-DAD and HPLC-MS analyses of the juices revealed that commercial juices contained the pomegranate tannin punicalagin (1500-1900 mg/L) while only traces of this compound were detected in the experimental juice obtained from arils in the laboratory. This shows that pomegranate industrial processing extracts some of the hydrolyzable tannins present in the fruit rind. This could account for the higher antioxidant activity of commercial juices compared to the experimental ones. In addition, anthocyanins, ellagic acid derivatives, and hydrolyzable tannins were detected and quantified in the pomegranate juices.
Article
Full-text available
The absorption and metabolism of anthocyanins (ACN) in humans was studied in four elderly women given 12 g elderberry extract (EBX) (720 mg total ACN), and six elderly women given 189 g lowbush blueberry (BB) (690 mg total ACN). The two major ACN in EBX, cyanidin-3-glucoside and cyanidin-3-sambubioside, as well as four metabolites: 1) peonidin 3-glucoside, 2) peonidin 3-sambubioside, 3) peonidin monoglucuronide, and 4) cyanidin-3-glucoside monoglucuronide were identified in urine within 4 h of consumption using HPLC-MS/MS with diode-array detector detection and retention time. Total EBX ACN excretion was 554 +/- 90 microg (mean +/- SD, n = 4) (0.077% of intake/4 h, wt/wt). In 5 of 6 women fed BB, urine samples contained ACN, which were identified as the original forms based upon comparisons to the BB food sample, which contained 24 ACN, 22 of which were identified by HPLC-MS/MS. Reasonable correlations between BB and urine proportions of the different ACN were obtained except for ACN arabinosides. Total urinary excretion during the first 6 h was 23.2 +/- 10.9 microg (mean +/- SD, n = 5) (0.004% of intake/6 h, wt/wt). Plasma ACN levels were below detection limits using 2 mL plasma in women that consumed BB. This study demonstrates for the first time that in vivo methylation of cyanidin to peonidin and glucuronide conjugate formation occurs after people consume ACN and demonstrates the low absorption and excretion of ACN compared with other flavonoids.
Article
Full-text available
Epidemiologic studies have linked flavonoid-rich foods with a reduced risk of cardiovascular mortality. Some cocoas are flavonoid-rich and contain the monomeric flavanols (-)-epicatechin and (+)-catechin and oligomeric procyanidins formed from these monomeric units. Both the monomers and the oligomers have shown potential in favorably influencing cardiovascular health in in vitro and preliminary clinical studies. Although previous investigations have shown increasing concentrations of (-)-epicatechin in human plasma after cocoa consumption, no information is available in the published literature regarding the presence of procyanidins in human plasma. This study sought to determine whether procyanidins can be detected and quantified in human plasma after acute consumption of a flavanol-rich cocoa. Peripheral blood was obtained from 5 healthy adult subjects before (baseline, 0 h) and 0.5, 2, and 6 h after consumption of 0.375 g cocoa/kg body wt as a beverage. Plasma samples were analyzed for monomers and procyanidins with the use of reversed-phase HPLC with coulometric electrochemical array detection and liquid chromatography-tandem mass spectrometry. Procyanidin dimer, (-)-epicatechin, and (+)-catechin were detected in the plasma of human subjects as early as 0.5 h (16 +/- 5 nmol/L, 2.61 +/- 0.46 micro mol/L, and 0.13 +/- 0.03 micro mol/L, respectively) after acute cocoa consumption and reached maximal concentrations by 2 h (41 +/- 4 nmol/L, 5.92 +/- 0.60 micro mol/L, and 0.16 +/- 0.03 micro mol/L, respectively). Dimeric procyanidins can be detected in human plasma as early as 30 min after the consumption of a flavanol-rich food such as cocoa.
Article
Full-text available
Quantification of ellagic acid, the principal bioactive component of pomegranate leaf extract, in rats plasma following oral administration of pomegranate leaf extract was achieved by using a high-performance liquid chromatographic method. The calibration curve for ellagic acid was linear (r2=0.9998) ver the concentration range 0.026-1.3 microg/ml. The intra- and inter-day assays of ellagic acid from rat plasma were less than 6.52% at concentration range from 26 to 1300 ng/ml and good overall recoveries (94.5-102.4%) were found on same concentrations. The concentration-time profile was fitted with an open two-compartment system with lag time and its max concentration of ellagic acid in plasma was 213 ng/ml only 0.55 h after oral administration extract 0.8 g/kg. The pharmacokinetic profile indicates that ellagic acid has poor absorption and rapid elimination after oral administration pomegranate leaf extract, and part of it was absorbed from stomach.
Article
Full-text available
For some classes of dietary polyphenols, there are now sufficient intervention studies to indicate the type and magnitude of effects among humans in vivo, on the basis of short-term changes in biomarkers. Isoflavones (genistein and daidzein, found in soy) have significant effects on bone health among postmenopausal women, together with some weak hormonal effects. Monomeric catechins (found at especially high concentrations in tea) have effects on plasma antioxidant biomarkers and energy metabolism. Procyanidins (oligomeric catechins found at high concentrations in red wine, grapes, cocoa, cranberries, apples, and some supplements such as Pycnogenol) have pronounced effects on the vascular system, including but not limited to plasma antioxidant activity. Quercetin (the main representative of the flavonol class, found at high concentrations in onions, apples, red wine, broccoli, tea, and Ginkgo biloba) influences some carcinogenesis markers and has small effects on plasma antioxidant biomarkers in vivo, although some studies failed to find this effect. Compared with the effects of polyphenols in vitro, the effects in vivo, although significant, are more limited. The reasons for this are 1) lack of validated in vivo biomarkers, especially in the area of carcinogenesis; 2) lack of long-term studies; and 3) lack of understanding or consideration of bioavailability in the in vitro studies, which are subsequently used for the design of in vivo experiments. It is time to rethink the design of in vitro and in vivo studies, so that these issues are carefully considered. The length of human intervention studies should be increased, to more closely reflect the long-term dietary consumption of polyphenols.
Article
Full-text available
Research has shown that fruits and vegetables containing high levels of polyphenolics (flavonoids) display high total antioxidant activity. Our laboratory found that various fruit and vegetable extracts, particularly blueberry (BB), were effective in reversing age-related deficits in neuronal signaling and behavioral parameters following 8 weeks of feeding, possibly due to their polyphenolic content. However, it was unclear if these phytonutrients were able to directly access the brain from dietary BB supplementation (BBS). The present study examined whether different classes of polyphenols could be found in brain areas associated with cognitive performance following BBS. Thus, 19 month old F344 rats were fed a control or 2% BB diet for 8-10 weeks and tested in the Morris water maze (MWM), a measure of spatial learning and memory. LC-MS analyses of anthocyanins in the diet and subsequently in different brain regions of BBS and control rats were carried out. Several anthocyanins (cyanidin-3-O-beta-galactoside, cyanidin-3-O-beta-glucoside, cyanidin-3-O-beta-arabinose, malvidin-3-O-beta-galactoside, malvidin-3-O-beta-glucoside, malvidin-3-O-beta-arabinose, peonidin-3-O-beta-arabinose and delphinidin-3-O-beta-galactoside) were found in the cerebellum, cortex, hippocampus or striatum of the BBS rats, but not the controls. These findings are the first to suggest that polyphenolic compounds are able to cross the blood brain barrier and localize in various brain regions important for learning and memory. Correlational analyses revealed a relationship between MWM performance in BBS rats and the total number of anthocyanin compounds found in the cortex. These findings suggest that these compounds may deliver their antioxidant and signaling modifying capabilities centrally.
Article
Full-text available
Rats were fed a grape seed extract (GSE) containing (+)-catechin, (-)-epicatechin and dimers, trimers, tetramers and polymeric procyanidins. Liver, kidney, brain and gastrointestinal (GI) tract together with plasma, urine and faeces were collected over a 24 h period and their flavan-3-ol content was analysed by HPLC with tandem mass spectrometry and diode array detection. Small amounts of the GSE flavan-3-ols moved out of the stomach and into the duodenum/jejunum, and to a greater extent the ileum 1 h after ingestion, and into the caecum after 2 h with relatively small amounts being detected in the colon after 3 h. The GI tract contained the parent GSE flavan-3-ols and procyanidins with only trace amounts of metabolites and there were no indications that proanthocyanidins were depolymerised in the GI tract releasing monomeric flavan-3-ols. Plasma contained exclusively catechin glucuronides and methylated glucuronide metabolites which were also detected in the liver and kidneys. These metabolites were also present in urine together with sulphated metabolites and low amounts of the procyanidin dimers B1, B2, B3 and B4 as well as the trimer C2 and an unknown GSE trimer. The amounts of (+)-catechin and (-)-epicatechin metabolites excreted in urine relative to the quantity of the monomers ingested were 27 and 36 %, respectively, after 24 h. This is similar to the levels of urinary excretion reported to occur by other investigators after feeding (-)-epicatechin to rats and provides further, albeit indirect, evidence that the procyanidin oligomers in the GSE were not depolymerised to monomers to any extent after ingestion. No convincing analytical data were obtained for the presence of flavan-3-ol metabolites in the brain.
Chapter
Atherosclerosis is the major cause of morbidity and mortality in the Western world, and its pathogenesis involves complicated interactions among cells of the arterial wall, blood cells, and plasma lipoproteins.
Article
Polyphenols are abundant micronutrients in our diet, and evidence for their role in the prevention of degenerative diseases is emerging. Bioavailability differs greatly from one polyphenol to another, so that the most abundant polyphenols in our diet are not necessarily those leading to the highest concentrations of active metabolites in target tissues. Mean values for the maximal plasma concentration, the time to reach the maximal plasma concentration, the area under the plasma concentration-time curve, the elimination half-life, and the relative urinary excretion were calculated for 18 major polyphenols. We used data from 97 studies that investigated the kinetics and extent of polyphenol absorption among adults, after ingestion of a single dose of polyphenol provided as pure compound, plant extract, or whole food/beverage. The metabolites present in blood, resulting from digestive and hepatic activity, usually differ from the native compounds. The nature of the known metabolites is described when data are available. The plasma concentrations of total metabolites ranged from 0 to 4 mumol/L with an intake of 50 mg aglycone equivalents, and the relative urinary excretion ranged from 0.3% to 43% of the ingested dose, depending on the polyphenol. Gallic acid and isoflavones are the most well-absorbed polyphenols, followed by catechins, flavanones, and quercetin glucosides, but with different kinetics. The least well-absorbed polyphenols are the proanthocyanidins, the galloylated tea catechins, and the anthocyanins. Data are still too limited for assessment of hydroxycinnamic acids and other polyphenols. These data may be useful for the design and interpretation of intervention studies investigating the health effects of polyphenols.
Article
Anthocyanins, which are natural plant pigments from the flavonoid family, represent substantiated constituents of the human diet. Many foods but especially red grapes and wines contain large amounts of flavonoids, which are mostly anthocyanins. The aim of our study was to determine the potential bioavailability, in human, of several anthocyanins from red wine. Six healthy, fasting volunteers, having a polyphenols-free diet, drank 300 mL of water every hour for 12 h and collected urine. Several weeks later, the same volunteers repeated the same procedure but replaced the water of the fourth drinking dose with white wine. Two weeks later, they repeated the procedure with red instead of white wine. In the 300 mL dose of red wine, the subjects received 218 mg of anthocyanins, which were detected in their urine by HPLC analysis with a photodiode array detector. Two of the compounds found among the wine anthocyanins were found unchanged in the urine. Other anthocyanin compounds, which seemed to have undergone molecular modifications, were detected in the urine after incubation with HCl. The anthocyanin level in the urine reached a peak within 6 h of the wine drinking. Within 12 h of the wine drinking, we found 1.5−5.1% of the ingested anthocyanins, in the urine. Keywords: Red wine; anthocyanins; antioxidants; absorption; urine; human
Article
Ellagic acid (EA), derived from fruit ellagitannins, is known to be antimutagenic and anticarcinogenic in various animal tumor models. In this study, EA at a dose of 4 g/kg diet inhibited multiplicity of tumors induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice by 54%. This inhibition was dose related between 0.06 and 4.0 g/kg diet. In contrast, two related compounds, esculin and esculetin, had no effect on lung tumorigenesis. The biodistribution of EA was studied as a function of dose and time after gavage of EA. The levels of EA in the lung were directly proportional to the dose of EA between 0.2 and 2.0 mmol. The maximum level of EA, corresponding to 21.3 nmol/g, was observed 30 minutes after gavage with 2.0 mmol of EA/kg body wt, which corresponds to only 70 ppm of the administered dose. The levels in liver tissues were 10-fold lower and reached a maximum 30 minutes after gavage. At this interval, the blood level of EA was 1 nmol/ml. The inclusion of EA in cyclodextrin doubles the level of EA in lung tissues. These results demonstrate that EA localizes preferentially in lung tissues and confirm that EA administered orally can inhibit lung tumorigenesis.
Article
A study was conducted to identify and characterise the toxic principle in Terminalia oblongata, commonly known as yellow-wood. Crude aqueous extracts of yellow-wood leaf were found to produce the same liver lesion in mice as has been reported in ruminants. The hepatotoxic fraction was isolated and identified as a hydrolysable vegetable tannin called punicalagin. When given orally, the dose required to produce toxicity was at least 20 times greater than when given intraperitoneally. Following a given dose of punicalagin, the onset and severity of liver necrosis was found to be related to the time interval after dosing. In addition to punicalagin, an unidentified nephrotoxic substance was found which was capable of producing avascular renal necrosis without liver necrosis.
Article
The effect of ellagic acid and some of its more lipophilic derivatives on the mutagenicity of (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenz[a]pyrene was examined in Salmonella typhimurium TA100. Ellagic acid, 3,3'-di-O-methylellagic acid, 4,4'-di-O-methylellagic acid and 3-O-decylellagic acid were found to have approximately equal antimutagenic activity. The tissue distribution and elimination of ellagic acid, 3,3'-di-O-methylellagic acid and 3-O-decylellagic acid were examined in CD-1 mice. Little or no ellagic acid (less than 1 nmol/g) was found in blood, lung or liver after the oral administration by gavage of 300 mumol of ellagic acid per kg body weight of after feeding 1% of ellagic acid in the diet for 1 week. Following the i.p. administration of 120 mumol/kg of ellagic acid, the blood and lung levels of ellagic acid were 15-20 nmol/g at 30 min after the dose, and the concentrations of ellagic acid decreased to 1-3 nmol/g at 6-8 h after the dose. A portion of the administered i.p. dose precipitated in the abdominal cavity. After i.v. administration, ellagic acid was eliminated very rapidly from blood, lung and liver, and approximately 70% of the administered dose was recovered in the urine and feces as free ellagic acid and its conjugates. At 2 h after an i.v. injection of 60 mumol/kg of ellagic acid, 46% of the dose was recovered in the urine as ellagic acid and its conjugates. Of this amount, about half was excreted as free ellagic acid and half was excreted as conjugates. An additional 25% of the dose was recovered in the feces (mostly as free ellagic acid) after 7 h. The disposition of 3,3'-di-O-methylellagic acid or 3-O-decylellagic acid after i.v. administration (32 mumol/kg) was examined and compared to the disposition of the same i.v. dose of ellagic acid. The concentrations of ellagic acid, 3,3'-di-O-methylellagic acid and 3-O-decylellagic acid decreased rapidly in the blood, liver and lung, but the concentrations of 3-O-decylellagic acid in the lung throughout the experimental period (2-360 min) was on average 20- to 40-fold higher than the corresponding average concentrations of ellagic acid or 3,3'-di-O-methylellagic acid.
Article
1. The absorption, distribution and elimination of 3H-ellagic acid, a putative antimutagen and anticarcinogen, was studied in male Swiss-Webster mice following oral administration. 2. Levels of 3H-ellagic acid were highest in blood 30 min after administration, in urine and bile 120 min post-administration, and in liver, lung and kidney 15 min after administration [corrected]. 3. Free ellagic acid and its conjugates were present in urine, bile and blood. H.p.l.c. analysis of the organic solvent extracts of urine, bile and blood indicated the presence of four metabolites in urine, two in blood and one in bile. 4. Sulphate ester, glucuronide and glutathione conjugates of ellagic acid were present in urine, bile and blood. H.p.l.c. analysis of organic solvent extracts after aryl sulphatase or beta-glucuronidase treatment showed that ellagic acid was the major component present. 5. Absorption of 3H-ellagic acid occurred mostly within two hours after oral administration. Levels in blood, bile and tissues were low and almost all of the absorbed dose was excreted in urine. 6. More than 53% of the orally administered 3H-ellagic acid remained in the gastrointestinal tract at 24 h. Approximately 19% was excreted in faeces and 22% in urine at 24 h. 7. Of the 24 h faecal radioactivity 93% was extractable into organic solvents and more than 80% of this fraction was free ellagic acid. Only one metabolite was found in faeces.
Article
1. Following oral administration of ellagic acid to the rat, 10% of the dose was excreted as 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one in urine and faeces. A second metabolite was detected in urine and faeces but not identified. Both metabolites were of microfloral origin, as their formation was not observed in germ-free rats but was demonstrated when ellagic acid was incubated in vitro with micro-organisms from rat gastro-intestinal tract. 2. Following intraperitoneal, but not oral, administration of ellagic acid, a third metabolite was detected in urine. 3. Unchanged ellagic acid was not detected in faeces or urine of any normal rat examined, but small amounts were detected in the faeces of germ-free animals. 4. Following oral administration of ellagic acid, two conjugates of 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one were detected in bile, whereas intraperitoneal administration resulted in the biliary excretion of three conjugates of an unidentified metabolite.
Article
Bioassay-guided fractionation of the MeOH extract of Pteropi faeces (the feces of Trogopterus xanthipes Milne-Edwards) furnished three hyaluronidase inhibitory active 6H-dibenzo[b,d]-pyran-6-ones (1-3), together with a new compound, 3,8,10-trihydroxy-6H-dibenzo[b,d]pyran-6-one (4). Their structures were established on the basis of the spectroscopic methods.
Article
Article
Gallocatechins and a range of prodelphinidins were purified by high performance liquid chromatography from pomegranate peel. Gallocatechin, gallocatechin-(4-8)-catechin, gallocatechin-(4-8)-gallocatechin and catechin-(4-8)-gallocatechin were all identified, purified and quantified by LC-DAD-MS and MS-MS. The antioxidant properties of these compounds were assessed using two methods: (i) inhibition of ascorbate/iron-induced peroxidation of phosphatidylcholine liposomes; and (ii) scavenging of the radical cation of 2,2-azinobis (3-ethyl-benzothiazoline-6-sulphonate, ABTS) relative to the water-soluble vitamin E analogue Trolox C (expressed as Trolox C equivalent antioxidant capacity, TEAC). The prodelphinidin dimers were potent antioxidants in the aqueous phase, being much more effective than the gallocatechin monomer. However, in the lipid phase, only one of the dimers (gallocatechin-(4-8)-catechin) was significantly more effective than the monomer in the inhibition of lipid peroxidation of phosphatidylcholine vesicles. This study represents the first report on the antioxidant properties of prodelphinidins.
Article
Considerable epidemiological evidence suggests a link between the consumption of diets rich in fruits and vegetables and a decreased risk of cardiovascular disease and cancers. Anthocyanins have received attention as important dietary constituents that may provide health benefits and contribute antioxidant capacity beyond that provided by essential micronutrients such as ascorbate, tocopherols, and selenium. The emergence of renewed interest by industrial countries in traditional herbal medicines and the development of 'functional foods' are stimulating the need for more information regarding the bioavailability and efficacy of plant polyphenols. Flavonoids represent a numerous group of secondary plant metabolites based on the structure of a pyran ring flanked by two or more phenyl rings and varying subtly in the degree of unsaturation and the pattern of hydroxylation or methylation. Flavonoids also vary in the type of sugar attached or the degree of polymerization. Anthocyanins, potent flavonoid antioxidants widely distributed in fruits, vegetables and red wines, normally occur in nature as glycosides, a form not usually considered as bioavailable. We have examined the bioavailability and pharmacokinetics of anthocyanins in humans. Anthocyanins were detected as glycosides in both plasma and urine samples. The elimination of plasma anthocyanins appeared to follow first-order kinetics and most anthocyanin compounds were excreted in urine within 4 h after feeding. The current findings appear to refute assumptions that anthocyanins are not absorbed in their unchanged glycosylated forms in humans.
Article
Flavanols are the most abundant flavonoids in the human diet where they exist as monomers, oligomers and polymers. In the present study, catechin, the procyanidin dimer B3 and a grape-seed extract containing catechin, epicatechin and a mixture of procyanidins were fed to rats in a single meal. After the meals, catechin and epicatechin were present in conjugated forms in both plasma and urine. In contrast, no procyanidins or conjugates were detected in the plasma or urine of any rats. Procyanidins were not cleaved into bioavailable monomers and had no significant effects on the plasma levels or urinary excretion of the monomers when supplied together in the grapeseed extract. We conclude that the nutritional effects of dietary procyanidins are unlikely to be due to procyanidins themselves or monomeric metabolites with the intact flavonoid-ring structure, as they do not exist at detectable concentrations in vivo. Future research should focus on other procyanidin metabolites such as phenolic acids and on the effects of the unabsorbed oligomers and polymers on the human gastrointestinal tract.
Article
Punicalagin is an antioxidant ellagitannin of pomegranate juice. This compound is responsible for the high antioxidant activity of this juice. Nothing is known about the bioavailability and metabolism of punicalagin or other food ellagitannins. The present work aims to evaluate the bioavailability and metabolism of punicalagin in the rat as an animal model. Two groups of rats were studied. One fed with standard rat diet (n = 5) and another with the same diet plus 6 % punicalagin (n = 5). Samples of urine and faeces were taken during 37 days and plasma every week. The different metabolites were analysed by HPLC-MS-MS. The daily intake of punicalagin ranged from 0.6 to 1.2 g. Values around 3-6 % the ingested punicalagin were excreted as identified metabolites in faeces and urine. In faeces, punicalagin is transformed to hydrolysis products and partly metabolites by the rat microflora to 6H-dibenzo[b,d]pyran-6-one derivatives. In plasma, punicalagin was detected at concentrations around 30 microg/mL, and glucuronides of methyl ether derivatives of ellagic acid were also detected. 6H-Dibenzo[b,d]pyran-6-one derivatives were also detected especially during the last few weeks of the experiment. In urine, the main metabolites observed were the 6H-dibenzo[b,d]pyran-6-one derivatives, as aglycones or glucuronides. As only 3-6 % of the ingested punicalagin was detected as such or as metabolites in urine and faeces, the majority of this ellagitannin has to be converted to undetectable metabolites (i. e. CO(2)) or accumulated in non-analysed tissues, however with only traces of punicalagin metabolites being detected in liver or kidney. This is the first report on the absorption of an ellagitannin and its presence in plasma. In addition, the transformation of ellagic acid derivatives to 6H-dibenzo[b,d]pyran-6-one derivatives in the rat is also confirmed.
Article
Anthocyanins are phenolic compounds widely distributed in fruits and vegetables. Their consumption has been shown to prevent some chronic diseases. Anthocyanin metabolism, however, is still not fully understood. The aim of this work was to evaluate the bioavailability of anthocyanins in humans consuming a meal containing strawberries and to identify possible metabolites in urine. Six healthy volunteers (three women and three men) consumed a meal containing 200 g strawberries (providing 179 micro mol pelargonidin-3-glucoside). Urine samples were collected before and after the meal and rapidly treated by solid-phase extraction. Identification and quantification of anthocyanin metabolites were carried out by HPLC-ESI-MS-MS and HPLC with UV-visible detection, respectively. In addition to pelargonidin-3-glucoside, five anthocyanin metabolites were identified in urine: three monoglucuronides of pelargonidin, one sulfoconjugate of pelargonidin and pelargonidin itself. Total urinary excretion of strawberry anthocyanin metabolites corresponded to 1.80 +/- 0.29% (mean +/- SEM, n = 6) of pelargonidin-3-glucoside ingested. More than 80% of this excretion was related to a monoglucuronide. Four hours after the meal, more than two-thirds of anthocyanin metabolites had been excreted, although urinary excretion of the metabolites continued until the end of the 24-h experiment. This study demonstrated that anthocyanins were glucuro- and sulfo-conjugated in humans and that the main metabolite of strawberry anthocyanins in human urine was a monoglucuronide of pelargonidin.
Article
The water-soluble ellagitanin punicalagin has been reported to be toxic to cattle. Taking into account that this antioxidant polyphenol is very abundant in pomegranate juice (> or =2 g/L), the present study evaluated the possible toxic effect of punicalagin in Sprague-Dawley rats upon repeated oral administration of a 6% punicalagin-containing diet for 37 days. Punicalagin and related metabolites were identified by HPLC-DAD-MS-MS in plasma, liver, and kidney. Five punicalagin-related metabolites were detected in liver and kidney, that is, two ellagic acid derivatives, gallagic acid, 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one glucuronide, and 3,8,10-trihydroxy-6H-dibenzo[b,d]pyran-6-one. Feedstuff intake, food utility index, and growth rate were lower in treated rats during the first 15 days without significant adverse effects, which could be due to the lower nutritional value of the punicalagin-enriched diet together with a decrease in its palatability (lower food intake). No significant differences were found in treated rats in any blood parameter analyzed (including the antioxidant enzymes gluthatione peroxidase and superoxide dismutase) with the exception of urea and triglycerides, which remained at low values throughout the experiment. Although the reason for the decrease is unclear, it could be due to the lower nutritional value of the punicalagin-enriched diet with respect to the standard rat food. Histopathological analysis of liver and kidney corroborated the absence of toxicity. In principle, the results reported here, together with the large safety margin considered, indicate the lack of toxic effect of punicalagin in rats during the 37 day period investigated. However, taking into account the high punicalagin content of pomegranate-derived foodstuffs, safety evaluation should be also carried out in humans with a lower dose and during a longer period of intake.
Article
To confirm the absorption of proanthocyanidin (PA) into the human body, four healthy adults were administered 2.0 g of PA-rich grape seed extract (GSE). Blood were drawn before intake and 2 h after intake. Through the enzymatic treatment of sulfatase and beta-glucuronidase, blood samples were analyzed by HPLC coupled with mass-spectrometry (LC/MS). Procyanidin B1 [epicatechin-(4beta-->8)-catechin] was detected in human serum 2 h after intake. Its concentration was 10.6 +/- 2.5 nmol/l.
Article
Ellagic acid (EA), a polyphenol present in many berries, has been demonstrated to be preventive of esophageal cancer in animals both at the initiation and promotion stages. To be able to extrapolate these findings to humans we have studied the transcellular absorption and epithelial cell accumulation of [14C]EA in the human intestinal Caco-2 cells. The apical (mucosal) to basolateral (serosal) transcellular transport of 10 microM [14C]EA was minimal with a P(app) of only 0.13 x 10(-6)cm/s, which is less than for the paracellular transport marker mannitol. In spite of observations of basolateral to apical efflux, Caco-2 cell uptake studies showed high accumulation of EA in the cells (1054+/-136 pmol/mg protein), indicating facile absorptive transport across the apical membrane. Surprisingly, as much as 93% of the cellular EA was irreversibly bound to macromolecules (982+/-151 pmol/mg protein). To confirm the irreversible nature of the binding to protein, Caco-2 cells treated with 10 microM [14C]EA were subjected to SDS-PAGE analysis. This resulted in radiolabeled protein bands trapped in the stacking gel, consistent with [14C]EA-crosslinked proteins. Treatment of Caco-2 cells with 10 microM [14C]EA also revealed irreversible binding of EA to cellular DNA as much as five times higher than for protein (5020+/-773 pmol/mg DNA). Whereas the irreversible binding to protein required oxidation of EA by reactive oxygen species, this did not seem to be the case with the DNA binding. The avid irreversible binding to cellular DNA and protein may be the reason for its highly limited transcellular absorption. Thus, EA appears to accumulate selectively in the epithelial cells of the aerodigestive tract, where its cancer preventive actions may be displayed.