In vitro study of the blood-brain barrier transport of bioactives from Mediterranean foods.

The Mediterranean diet (MD), characterized by olive oil, olives, fruits, vegetables, and wine intake, is associated with a reduced risk of dementia. These foods are rich in bioactives with neuroprotective and antioxidant properties, including hydroxytyrosol (HT), tyrosol (TYRS), serotonin (SER) and protocatechuic acid (PCA), a phenolic acid metabolite of anthocyanins. It remains to be established if these molecules cross the blood-brain barrier (BBB), a complex interface that strictly controls the entrance of molecules into the brain. We aimed to assess the ability of tyrosine (TYR), HT, TYRS, PCA and SER to pass through the BBB without disrupting its properties. Using Human Brain Microvascular Endothelial Cells as an in vitro model of the BBB, we assessed its integrity by transendothelial electrical resistance, paracellular permeability and immunocytochemical assays of the adherens junction protein ß-catenin. The transport across the BBB was evaluated by ultra-high-performance liquid chromatography high resolution mass spectrometry. Results show that tested bioactives did not impair BBB integrity regardless of the concentration evaluated. Additionally, all of them cross the BBB, with the following percentages: HT (∼70%), TYR (∼50%), TYRS (∼30%), SER (∼30%) and PCA (∼9%). These results provide a basis for the MD neuroprotective role.

Hydroxytyrosol and dopamine metabolites: Anti-aggregative effect and neuroprotective activity against α-synuclein-induced toxicity.

The abnormal aggregation of the α-synuclein (αsyn) protein is involved in the formation of Lewy bodies in the brain of patients suffering from Parkinson disease (PD). Hydroxytyrosol (HT), a polyphenolic compound present in olives, olive oil, and wine, has been shown to inhibit aggregation and destabilise the αsyn aggregates, preventing neuronal cell death. However, very limited data have been published on the study of its metabolites. Therefore, this study investigated the capacity of the metabolites 3,4-dihydroxyphenylacetaldehyde (DOPAL), 4-hydroxy-3-methoxyphenylethanol (MOPET), and 3-methoxy-4-hydroxyphenylacetaldehyde (MOPAL) to prevent the aggregation and toxic effects of αsyn fibrils. In vitro techniques, such as Thioflavin T (ThT), Transmission Electronic Microscopy (TEM), electrophoresis, thiazolyl blue tetrazolium bromide (MTT), and Real-Time PCR (RT-PCR) were used. Our results show that among these three metabolites, DOPAL exerts the greatest effect, preventing aggregation and αsyn-induced neurotoxicity. In fact, DOPAL has the ability to completely inhibit αsyn fibril formation at low doses. Moreover, this metabolite has a potent destabilising effect on the αsyn fibrils. Concerning neuroprotection, DOPAL can counteract the toxicity induced by αsyn. The vitagene expression results show a possible relationship between the neuroprotection mechanism exhibited by DOPAL and the modulation of SIRT-2 and Hsp70.

Chiroptical and potential in vitro anti-inflammatory properties of viniferin stereoisomers from grapevine (Vitis vinifera L.).

Determination of stereochemistry and enantiomeric excess in chiral natural molecules is a research of great interest because enantiomers can exhibit different biological activities. Viniferin stilbene dimers are natural molecules present in grape berries and wine but also, in larger amount, in stalks of grapevine. Four stereoisomers of viniferin stilbene dimers (7aS,8aS)-E-ε-viniferin (1a), (7aR,8aR)-E-ε-viniferin (1b), (7aS,8aR)-E-ω-viniferin (2a), and (7aR,8aS)-E-ω-viniferin (2b) were isolated from grapevine stalks of Cabernet Sauvignon, Merlot and Sauvignon Blanc, using a combination of centrifugal partition chromatography (CPC), preparative and chiral HPLC. The structure elucidation of these molecules was achieved by NMR whereas the absolute configurations of the four stereoisomers were investigated by vibrational circular dichroism spectroscopy in combination with density functional theory (DFT) calculations. This study unambiguously established the (+)-(7aS,8aS) and (+)-(7aR,8aS) configurations for E-ε-viniferin and E-ω-viniferin, respectively. Finally, we show that Cabernet Sauvignon provided the quasi enantiopure (+)-(7aS,8aS)-E-ε-viniferin compound which presents the best anti-inflammatory and anti-oxidant activities.

Oxyresveratrol and Gnetol Glucuronide Metabolites: Chemical Production, Structural Identification, Metabolism by Human and Rat Liver Fractions, and In Vitro Anti-inflammatory Properties.

Stilbene metabolites are attracting great interest because many of them exhibit similar or even stronger biological effects than their parent compounds. Furthermore, the metabolized forms are predominant in biological fluids; therefore, their study is highly relevant. After hemisynthesis production, isolation, and structural elucidation, three glucuronide metabolites for oxyresveratrol (ORV) were formed: trans-ORV-4'-O-glucuronide, trans-ORV-3-O-glucuronide, and trans-ORV-2'-O-glucuronide. In addition, two glucuronide metabolites were obtained for gnetol (GN): trans-GN-2'-O-glucuronide and trans-GN-3-O-glucuronide. When the metabolism of ORV and GN is studied in vitro by human and rat hepatic enzymes, four of the five hemisynthesized compounds were identified and quantified. Human enzymes glucuronidated preferably at the C-2' position, whereas rat enzymes do so at the C-3 position. In view of these kinetic findings, rat enzymes have a stronger metabolic capacity than human enzymes. Finally, ORV, GN, and their glucuronide metabolites (mainly at the C-3 position) decreased nitric oxide, reactive oxygen species, interleukin 1ß, and tumor necrosis factor α production in lipopolysaccharide-stimulated macrophages.

Anti-VEGF Effect of Bioactive Indolic Compounds and Hydroxytyrosol Metabolites.

Angiogenesis is a key process involved in both cancer and cardiovascular diseases, the vascular endothelial growth factor (VEGF) and its VEGF receptor-2 (VEGFR-2) being the main triggers. The aim of this study was to determine the molecular mechanism underlying the potent inhibition of VEGF signaling by hydroxytyrosol (HT) metabolites and indolic compounds and establish a relation between their structure and bioactivity. Experiments involved the evaluation of their potential to inhibit VEGF on human umbilical vein endothelial cells (HUVECs) by ELISA assay and their subsequent effect on the downstream signaling pathway (PLCγ1, Akt, and endothelial nitric oxide synthetase (eNOS)) by Western blot. Respectively, 3,4-dihydroxyphenylacetaldehyde (DOPAL) (100 µM) and indole pyruvic acid (IPy) (1 mM) were capable of inhibiting VEGFR-2 activation with an IC50 value of 119 µM and 1.037 mM. The anti-angiogenic effect of DOPAL and IPy is mediated via PLCγ1. Additionally, DOPAL significantly increases eNOS phosphorylation, while IPy maintained it. These data provide for the first time evidence of the anti-angiogenic effect of DOPAL and IPy for future use as potential bioactive food ingredients.

Polyphenolic Characterization of Merlot, Tannat and Syrah Skin Extracts at Different Degrees of Maturity and Anti-Inflammatory Potential in RAW 264.7 Cells.

(1) Background: Both sensory quality and healthy attributes of Vitis vinifera grapes used for winemaking are closely related with the polyphenolic composition of their skins. (2) Methods: In this study, the polyphenolic characterization (flavan-3-ols, procyanidins, flavonols, stilbenes, anthocyanins) was investigated by ultra performance liquid chromatography coupled to a triple quadrupole mass spectrometer (UPLC-QqQ-MS). Skins from Vitis vinifera Merlot, Tannat, and Syrah red grape varieties cultivated in the south of France at different stages of ripening in 2018 were used. The anti-inflammatory and the antioxidant potential of the extracts were evaluated by the measure of nitric oxide (NO) and the intracellular reactive oxygen species production (ROS) in lipopolysaccharide (LPS)-stimulated macrophages. (3) Results: 41 polyphenols were quantified in all samples. Generally, the flavan-3-ol and procyanidin content decreased during ripening whereas the anthocyanins and stilbenes increased. In addition, as a novelty of this work, a wide identification and characterization of monomeric and oligomeric stilbenes was assessed by using authentic standards isolated in our laboratory, some of them (parthenocissin A and miyabenol C) reported for the first time in Merlot, Tannat and Syrah cultivars. The before-veraison skin extracts of all studied varieties, exhibited higher NO and ROS productions inhibition (>50%) proving both antioxidant and anti-inflammatory properties.

New Insights into the Exploitation of Vitis vinifera L. cv. Aglianico Leaf Extracts for Nutraceutical Purposes.

The leaves of Vitis vinifera L. have been used for a long time in traditional medicine for the treatment of many ailments. Grape polyphenols, indeed, have been demonstrated to be able to defend against oxidative stress, responsible for various disorders such as cancer, diabetes and neurodegenerative diseases. The effects of different extraction techniques, Soxhlet (SOX), Accelerated Solvent (ASE 40, ASE 50) and Ultrasound Assisted Extraction (UAE) were studied in this work to evaluate their impact on the chemical profile and bioactive potential of Vitis vinifera L. (cv. Aglianico) leaf extracts. The phytochemical profile was investigated by HPLC-DAD and 9 phenolic compounds were identified and quantified in the extract. Moreover, the antioxidant, anticholinesterase and antityrosinase activities were evaluated. In detail, the total polyphenol content and antioxidant activity (2,2-diphenyl-1-picrylhydrazyl, Oxygen Radical Absorbance Capacities and ß-Carotene Bleaching assays) were evaluated and compared to assess the Relative Antioxidant Capacity Index (RACI). To test the inhibitory activity of extracts towards cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition assays were performed. SOX and ASE 50 have shown the highest value of RACI, 0.76 and 0.65, respectively. Regarding enzymatic inhibitory activity, ASE 50 (IC50 = 107.16 ± 8.12 µg/mL) and SOX (IC50 = 171.34 ± 12.12 µg/mL) extracts exhibited the highest AChE and BChE inhibitory activity, respectively, while UAE (IC50 = 293.2 ± 25.6 µg/mL, followed by SOX (IC50 = 302.5 ± 38.3 µg/mL) showed the highest tyrosinase inhibition value. Our results demonstrated for the first time that Aglianico leaves are important sources of phenols that could be used to prevent oxidative stress and be potentially helpful in diseases treatable with tyrosinase and cholinesterase inhibitors, like myasthenia gravis or Alzheimer's.

α-Glucosidase Inhibitory Activity of Tannat Grape Phenolic Extracts in Relation to Their Ripening Stages.

The present study aimed to screen grape extracts as novel α-glucosidase inhibitors to prevent type-2 diabetes and hyperglycemia. The total polyphenol content (TPC) was measured by Folin-Ciocalteu assay and the stilbene, anthocyanin and flavan-3-ol compounds were measured by Ultra High-Performance Liquid Chromatography coupled to Mass Spectrometry (UHPLC-MS). The α-glucosidase inhibitory of seed and skin Tannat grape extracts at four ripening stages were investigated. The highest TPC values were measured in seeds at the "veraison stage" (65.29 ± 5.33 g of Gallic Acid Equivalent (GAE) per kilogram of Fresh Weight (FW)). This was in accordance with the high flavan-3-ol contents measured for these two extracts (43.22 ± 2.59 and 45.45 ± 6.48 g/kg of seeds FW, respectively). The skin and seed extracts at the first stage of ripening exerted strong α-glucosidase inhibition, exceeding 95% (p < 0.05). A high linear correlation (R = 0.723, p ≤ 0.05) was observed between flavan-3-ol contents and the α-glucosidase inhibitory activity. The stilbene contents and this activity were moderately to strongly anti-correlated (R = -0.828, p ≤ 0.05 for trans-resveratrol). The enzyme kinetic studies revealed a mixed type of inhibition. This study brings promising results for the therapeutic potential of seed and skin Tannat grape extracts as a functional food product with anti-diabetic activity.

Anthocyanins in Blueberries Grown in Hot Climate Exert Strong Antioxidant Activity and May Be Effective against Urinary Tract Bacteria.

Anthocyanins are extensively studied for their health-related properties, including antibacterial activity against urinary tract infections (UTI). Among common fruits, blueberries, with their remarkable antioxidant capacity, are one of the richest sources. Anthocyanin-rich extracts were obtained from four varieties: Snowchaser, Star, Stella Blue and Cristina Blue, grown in the hot climate of Southern Spain. Their total anthocyanins contents (TAC) were determined spectrophotometrically, and the anthocyanin profile by ultra high performance liquid chromatography - tandem mass spectrometer (UHPLC-MS/MS). Their antioxidant activity was assessed by oxygen radical absorbance capacity (ORAC) assay, while antibacterial activity against strains isolated from UTI patients was assessed in vitro, helping to select the varieties with the highest bioactive potential. Star showed the highest TAC and antioxidant activity (1663 ± 159 mg of cyanidin-3-O-glucoside (cy-3-O-glu) equivalents/100 g fresh weight (FW), 6345 ± 601 µmol Trolox equivalents (TE)/100 g FW, respectively), followed by Cristina Blue, Stella Blue and Snowchaser. As far as we know, this is the first time that cyanidin-3-rutinoside has been identified in blueberries. The extracts inhibited all the tested strains, MICs ranging from 0.4 mg/mL (for Stella Blue extract against UTI P. aeruginosa) to 9.5 mg/mL (for all extracts against UTI K. pneumoniae ssp. pneumoniae). This is the first study that assessed in vitro the antibacterial activity of blueberries against Klebsiella pneumoniae, Providencia stuartii and Micrococcus spp. strains isolated from UTI.

Resveratrol transformation in red wine after heat treatment.

Resveratrol is a well-known wine constituent. Its concentration can vary according to the cultivar choice and the winemaking process. Due to its phenolic structure, resveratrol could be transformed under high temperature or oxidative conditions, leading to the formation of various derivatives including oligomers. Hence, the goal of this study is to investigate the presence of these derivatives in wine. In the first stage, hemisynthesis of oligomeric stilbenes was achieved from resveratrol in ethanol by oxidative coupling using metals. Four de novo synthetized resveratrol derivatives were identified by MS and NMR spectroscopy including two new molecules, oxistilbenin F and oxistilbenin G. In the second stage, analysis of red wine after heat treatment by LC-MS confirmed the presence of some of these compounds in wine. Finally, the anti-inflammatory effects of the compounds were evaluated by studying their ability to prevent lipopolysaccharide (LPS)-induced upregulation of nitric oxide (NO) and reactive oxygen species (ROS) production in RAW 264.7 macrophage cell line.

Chemical hazards in grapes and wine, climate change and challenges to face.

Climate change has an impact on the chemical risks associated to wine consumption related with grape development and microbial contamination. We can classify chemical hazards in wine into two groups: those present in grapes due to agricultural practices, environmental contamination or fungal growth and those coming from fermentation and the winemaking process. The first group includes mycotoxins, whilst the second encompasses ethyl carbamate, biogenic amines, sulfur dioxide and proteins used as technological ingredients such as fining material. Usually the effective control of chemical hazards is achieved by assuring that they either are minimized or absent in the final product since their removal is somewhat difficult and sometimes it may affect sensory properties, which is a major issue in wine. Interestingly, it is possible to give recommendations to avoid excess of these compounds, but more research is needed to face future challenges related to climate change and consumer demands.

Anti-VEGF Signalling Mechanism in HUVECs by Melatonin, Serotonin, Hydroxytyrosol and Other Bioactive Compounds.

Angiogenesis drives evolution and destabilisation of atherosclerotic plaques and the growth and expansion of tumour cells. Vascular endothelial growth factor (VEGF) is the main endogenous pro-angiogenic factor in humans. The aim was to provide insight into the anti-VEGF activity of bioactive compounds derived from aromatic amino acids (serotonin, melatonin, 3-indoleacetic acid, 5-hydroxytryptophol and hydroxytyrosol). Experiments involved endothelial cell migration (wound-healing assay), the molecular mechanisms (ELISA assay) and the downstream effects (phospholipase C gamma 1 (PLCγ1), protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS) by Western blot) on human umbilical vein endothelial cells (HUVECs). The data suggest for the first time that hydroxytyrosol interacts with surface components of the endothelial cell membrane (, preventing VEGF from activating its receptor. Serotonin and 5-hydroxytryptophol significantly inhibited HUVEC migration (98% and 50%, respectively) following the same mechanism. Conversely to other bioactive compounds, the anti-angiogenic effect of melatonin, serotonin, 3-indoleacetic acid and 5-hydroxytryptophol is not mediated via PLCγ1. However, hydroxytyrosol inhibits PLCγ1 phosphorylation. Additionally, melatonin and serotonin maintained eNOS phosphorylation and hydroxytyrosol significantly activated eNOS-all via Akt. These data provide new evidence supporting the interest in melatonin, serotonin, 3-indoleacetic acid, 5-hydroxytryptophol and hydroxytyrosol for their further exploitation as anti-VEGF ingredients in food.

Melatonin, protocatechuic acid and hydroxytyrosol effects on vitagenes system against alpha-synuclein toxicity.

Preventing the abnormal assembly of α-synuclein (α-Syn) and the correct modulation of vitagenes system exercise strong neuroprotective effects. It has been reported that melatonin (MEL), protocatechuic acid (PCA) and hydroxytyrosol (HT) reduce α-Syn toxicity. Their effect on the vitagenes system of PC12 cells have not been explored yet. These bioactive can cross the blood brain barrier (BBB). Therefore, this work aims to evaluate the inhibitory and destabilising capacities of MEL, PCA, HT, and their combinations on α-Syn kinetics and effects on vitagenes system (sirtuin-1 (SIRT-1), sirtuin-2 (SIRT-2), heme oxygenase (HO-1) and heat shock protein 70 (Hsp-70)). In vitro techniques (Thioflavin T (ThT), Transmission Electronic Microscopy (TEM), electrophoresis, MTT assay and qPCR) were used. Compounds, both individually and simultaneously were able to decrease the toxicity induced by α-Syn. Concurrently, occurrence of PCA (100 µM) +HT (100 µM) showed the highest inhibitory effect against α-Syn fibril formation and destabilisation of α-Syn fibrils (88 and 62%, respectively). Moreover, these compounds increased the expression of SIRT-2, HO-1 and Hsp70, contributing to a neuroprotective effect. In addition, the most important result is the increase on the expression of SIRT-2 caused by the combination of MEL + HT + PCA in the absence of α-Syn fibrils.

Hydroxytyrosol protects from aging process via AMPK and autophagy; a review of its effects on cancer, metabolic syndrome, osteoporosis, immune-mediated and neurodegenerative diseases.

Aging is a complex process. It is considered a risk factor for several diseases such as cancer, neurodegenerative diseases, cardiovascular diseases, and diabetes, most of which have an oxidative and inflammatory base. Given that life expectancy is increasing, there is a present interest in the search for anti-aging strategies that allow a healthy aging. Interestingly, in Spain, where the Mediterranean Diet (MD) is the reference food pattern, life expectancy will have the highest average by 2040. This diet is characterized, among other items, by virgin olive oil intake, which contains between 50-200 mg/kg of hydroxytyrosol, a major polyphenolic component of olive oil. Hydroxytyrosol is formed by the hydrolysis of oleuropein during the maturing of olives, storage of olive oil, and preparation of table olives. It is a yield of oleuropein by microbiota action in the organism after virgin olive oil consumption. The daily intake in context of the MD is estimated to be around 0.15 and 30 mg/day. In the last few years, hydroxytyrosol has received increasing attention due to its multiple pharmacological activities, such as antioxidant, anti-inflammatory and pro-apoptotic activities. It has also been the focus of extensive research regarding its bioactivity. In this sense, hydroxytyrosol is under consideration for the development of new anti-aging strategies. In this review we will summarize the potential anti-aging effects of hydroxytyrosol and its protective role in several age-related diseases.

Hydroxytyrosol Decreases LPS- and α-Synuclein-Induced Microglial Activation In Vitro.

Neuroinflammation is a common feature shared by neurodegenerative disorders, such as Parkinson's disease (PD), and seems to play a key role in their development and progression. Microglia cells, the principal orchestrators of neuroinflammation, can be polarized in different phenotypes, which means they are able to have anti-inflammatory, pro-inflammatory, or neurodegenerative effects. Increasing evidence supports that the traditional Mediterranean dietary pattern is related to the reduction of cognitive decline in neurodegenerative diseases. A considerable intake of plant foods, fish, and extra virgin olive oil (EVOO), as well as a moderate consumption of red wine, all characteristic of the Mediterranean diet (MD), are behind these effects. These foods are especially rich in polyphenols, being the most relevant in the MD hydroxytyrosol (HT) and their derivatives present in EVOO, which have demonstrated a wide array of biological activities. Here, we demonstrate that HT is able to reduce the inflammation induced by two different stimuli: lipopolysaccharide and α-synuclein. We also study the possible molecular mechanisms involved in the anti-inflammatory effect of HT, including the study of nuclear factor kappa B (NF-кB), mitogen-activated protein kinases (MAPKs), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and inflammasome. Our data support the use of HT to prevent the inflammation associated with PD and shed light into the relationship between MD and this neurological disorder.

Chondroprotective Properties of Human-Enriched Serum Following Polyphenol Extract Absorption: Results from an Exploratory Clinical Trial.

Polyphenols are widely acknowledged for their health benefits, especially for the prevention of inflammatory and age-related diseases. We previously demonstrated that hydroxytyrosol (HT) and procyanidins (PCy), alone or in combination, drive preventive anti-osteoathritic effects in vivo. However, the lack of sufficient clinical evidences on the relationship between dietary phytochemicals and osteoarthritis remains. In this light, we investigated in humans the potential osteoarticular benefit of a grapeseed and olive extract (OPCO) characterized for its hydroxytyrosol (HT) and procyanidins (PCy) content. We first validated, in vitro, the anti-inflammatory and chondroprotective properties of the extract on primary cultured human articular chondrocytes stimulated by interleukin-1 beta (IL-1 ß). The sparing effect involved a molecular mechanism dependent on the nuclear transcription factor-kappa B (NF-κB) pathway. To confirm the clinical relevance of such a nutritional strategy, we designed an innovative clinical approach taking into account the metabolites that are formed during the digestion process and that appear in circulation after the ingestion of the OPCO extract. Blood samples from volunteers were collected following ingestion, absorption, and metabolization of the extract and then were processed and applied on human primary chondrocyte cultures. This original ex vivo methodology confirmed at a clinical level the chondroprotective properties previously observed in vitro and in vivo.

Phenolic Compounds Characteristic of the Mediterranean Diet in Mitigating Microglia-Mediated Neuroinflammation.

Neuroinflammation is a pathological feature of quite a number of Central Nervous System diseases such as Alzheimer and Parkinson's disease among others. The hallmark of brain neuroinflammation is the activation of microglia, which are the immune resident cells in the brain and represents the first line of defense when injury or disease occur. Microglial activated cells can adopt different phenotypes to carry out its diverse functions. Thus, the shift into pro-inflammatory/neurotoxic or anti-inflammatory/neuroprotective phenotypes, depending of the brain environment, has totally changed the understanding of microglia in neurodegenerative disease. For this reason, novel therapeutic strategies which aim to modify the microglia polarization are being developed. Additionally, the understanding of how nutrition may influence the prevention and/or treatment of neurodegenerative diseases has grown greatly in recent years. The protective role of Mediterranean diet (MD) in preventing neurodegenerative diseases has been reported in a number of studies. The Mediterranean dietary pattern includes as distinctive features the moderate intake of red wine and extra virgin olive oil, both of them rich in polyphenolic compounds, such as resveratrol, oleuropein and hydroxytyrosol and their derivatives, which have demonstrated anti-inflammatory effects on microglia on in vitro studies. This review summarizes our understanding of the role of dietary phenolic compounds characteristic of the MD in mitigating microglia-mediated neuroinflammation, including explanation regarding their bioavailability, metabolism and blood-brain barrier.

Tissular Distribution and Metabolism of trans-ε-Viniferin after Intraperitoneal Injection in Rat.

BACKGROUND: Recent studies showed that trans-ε-viniferin (ε-viniferin), a trans-resveratrol dehydrodimer, has anti-inflammatory and anti-obesity effects in rodents. The main purpose of this work was to assess the tissue distribution study of ε-viniferin and its metabolites after intraperitoneal (IP) administration in rat. METHODS: After IP injection of 50 mg/kg, ε-viniferin and its metabolites were identified and quantified in plasma, liver, kidneys, adipose tissues, urine, and faeces by Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS). RESULTS: ε-Viniferin underwent a rapid hepatic metabolism mostly to glucuronides but also to a lesser extent to sulphate derivatives. The highest glucuronide concentrations were found in liver followed by plasma and kidneys whereas only traces amounts were found in adipose tissues. In contrast the highest ε-viniferin areas under concentration (AUC) and mean residence times (MRT) values were found in white adipose tissues. Finally, much lower levels of ε-viniferin or its metabolites were found in urine than in faeces, suggesting that biliary excretion is the main elimination pathway. CONCLUSION: A rapid and large metabolism of ε-viniferin and a high bioaccumulation in white adipose tissues were observed. Thus, these tissues could be a reservoir of the native form of ε-viniferin that could allow its slow release and a sustained presence within the organism.