Tristan P. Dew

Effects of resveratrol alone or in combination with piperine on cerebral blood flow parameters and cognitive performance in human subjects: a randomised, double-blind, placebo-controlled, cross-over investigation

Previous research has shown that resveratrol can increase cerebral blood flow (CBF) in the absence of improved cognitive performance in healthy, young human subjects during the performance of cognitively demanding tasks. This lack of cognitive effects may be due to low bioavailability and, in turn, reduced bioefficacy of resveratrol in vivo. Piperine can alter polyphenol pharmacokinetics, but previous studies have not investigated whether this affects the efficacy of the target compound. Therefore, the objective of the present study was to ascertain whether co-supplementation of piperine with resveratrol affects the bioavailability and efficacy of resveratrol with regard to cognition and CBF. The present study utilised a randomised, double-blind, placebo-controlled, within-subjects design, where twenty-three adults were given placebo, trans-resveratrol (250 mg) and trans-resveratrol with 20 mg piperine on separate days at least a week apart. After a 40 min rest/absorption period, the participants performed a selection of cognitive tasks and CBF was assessed throughout the period, in the frontal cortex, using near-IR spectroscopy. The presence of resveratrol and its conjugates in the plasma was confirmed by liquid chromatography-MS analysis carried out following the administration of the same doses in a separate cohort (n 6). The results indicated that when co-supplemented, piperine and resveratrol significantly augmented CBF during task performance in comparison with placebo and resveratrol alone. Cognitive function, mood and blood pressure were not affected. The plasma concentrations of resveratrol and its metabolites were not significantly different between the treatments, which indicates that co-supplementation of piperine with resveratrol enhances the bioefficacy of resveratrol with regard to CBF effects, but not cognitive performance, and does this without altering bioavailability.

Absorption and metabolism of chlorogenic acids in cultured gastric epithelial monolayers

Gastric absorption of feruloylquinic acid and di-O-caffeoylquinic acid analogs has never been investigated despite their potential contribution to the proposed beneficial health effects leading to reduced risk of type 2 diabetes. Using a cultured gastric epithelial model, with an acidic apical pH, the relative permeability coefficients (Papp) and metabolic fate of a series of chlorogenic acids (CGAs) were investigated. Mechanistic studies were performed in the apical to basal direction and demonstrated differential rates of absorption for different CGA subgroups. For the first time, we show intact absorption of feruloylquinic acids and caffeoylquinic acid lactones across the gastric epithelium (Papp ∼ 0.2 cm/s). Transport seemed to be mainly by passive diffusion, because good linearity was observed over the incubation period and test concentrations, and we speculate that a potential carrier-mediated component may be involved in uptake of certain 4-acyl CGA isomers. In contrast, absorption of intact di-O-caffeoylquinic acids was rapid (Papp ∼ 2–10 cm/s) but nonlinear with respect to time and concentration dependence, which was potentially limited by interaction with an efflux transporter and/or pH gradient dependence. For the first time, methylation is shown in gastric mucosa. Furthermore, isoferulic acid, dimethoxycinnamic acid, and ferulic acid were identified as novel gastric metabolites of CGA biotransformation. We propose that the stomach is the first location for the release of hydroxycinnamic acids, which could explain their early detection after coffee consumption.

Oral green tea catechin metabolites are incorporated into human skin and protect against UV radiation-induced cutaneous inflammation in association with reduced production of pro-inflammatory eicosanoid 12-hydroxyeicosatetraenoic acid

Green tea catechins (GTC) reduce UV radiation (UVR)-induced inflammation in experimental models, but human studies are scarce and their cutaneous bioavailability and mechanism of photoprotection are unknown. We aimed to examine oral GTC cutaneous uptake, ability to protect human skin against erythema induced by a UVR dose range and impact on potent cyclo-oxygenase- and lipoxygenase-produced mediators of UVR inflammation, PGE2 and 12-hydroxyeicosatetraenoic acid (12-HETE), respectively. In an open oral intervention study, sixteen healthy human subjects (phototype I/II) were given low-dose GTC (540 mg) with vitamin C (50 mg) daily for 12 weeks. Pre- and post-supplementation, the buttock skin was exposed to UVR and the resultant erythema quantified. Skin blister fluid and biopsies were taken from the unexposed and the UVR-exposed skin 24 h after a pro-inflammatory UVR challenge (three minimal erythema doses). Urine, skin tissue and fluid were analysed for catechin content and skin fluid for PGE2 and 12-HETE by liquid chromatography coupled to tandem MS. A total of fourteen completing subjects were supplement compliant (twelve female, median 42.5 years, range 29-59 years). Benzoic acid levels were increased in skin fluid post-supplementation (P= 0.03), and methylated gallic acid and several intact catechins and hydroxyphenyl-valerolactones were detected in the skin tissue and fluid. AUC analysis for UVR erythema revealed reduced response post-GTC (P= 0.037). Pre-supplementation, PGE2 and 12-HETE were UVR induced (P= 0.003, 0.0001). After GTC, UVR-induced 12-HETE reduced from mean 64 (sd 42) to 41 (sd 32) pg/μl (P= 0.01), while PGE2 was unaltered. Thus, GTC intake results in the incorporation of catechin metabolites into human skin associated with abrogated UVR-induced 12-HETE; this may contribute to protection against sunburn inflammation and potentially longer-term UVR-mediated damage.

Urinary metabolite profiling identifies novel colonic metabolites and conjugates of phenolics in healthy volunteers

SCOPE The colonic metabolism of dietary flavonoids, phenolic acids and their phenolic metabolites is complex and many metabolites and conjugates have not yet been unambiguously identified in humans. METHODS AND RESULTS Urine samples from nine healthy human volunteers obtained after the ingestion of a puree of five (poly)phenol-rich berry fruits were analysed using LC-Orbitrap MS to provide a preliminary indication of possible metabolites based on exact mass. In most cases, the identity of compounds was confirmed using standards produced either chemically or enzymically followed by analysis using LC-triple quadrupole MS. Sulphated, glucuronidated and methylated forms of catechol, pyrogallol and protocatechuic acid mostly appeared in urine after 8 h, suggesting colonic metabolism. Gallic acid and (-)-epicatechin conjugates appeared mainly before 4 h, indicative of absorption from the small intestine. Conjugates of ferulic, caffeic, and vanillic acid appeared at intermediate times. CONCLUSION We have positively identified metabolites and conjugates, some novel, in the urine of healthy volunteers after intake of multiple phenolics from a mixed puree from berry fruits, with each being excreted at specific and signature times. Some of these compounds could potentially be used as biomarkers of fruit intake. The possible biological activities of these colonic metabolites require further assessment.

Influence of combined biotic and abiotic stress on nutritional quality parameters in tomato (Solanum lycopersicum).

Induction of abiotic stress in tomato plants has been proposed as a mechanism for improving the nutritional quality of fruits. However, the occurrence of biotic stress can interfere with normal abiotic stress responses. In this study, the combined effect of water stress and infection with plant-parasitic nematodes on the nutritional quality of tomato was investigated. Plants were exposed to one or both stresses, and the levels of phenolic compounds, carotenoids, and sugars in fruits were analyzed as well as physiological responses. Levels of carotenoids lycopene and β-carotene were lower in water-stressed tomatoes but exhibited a different response pattern under combined stress. Nematode stress was associated with increased flavonoid levels, albeit with reduced yields, while chlorogenic acid was increased by nematodes, water stress, and the combined stress. Sugar levels were higher only in tomatoes exposed to both stresses. These results emphasize the importance of studying plant stress factors in combination.

Epigallocatechin-3-gallate inhibits lactase but is alleviated by salivary proline-rich proteins.

Lactase phlorizin hydrolase is a small intestinal brush border enzyme that catalyzes the hydrolysis of the milk sugar, lactose, and also many flavonoid glucosides. We demonstrate that epigallocatechin-3-gallate (EGCG), the principal flavonoid from green tea, inhibits in vitro hydrolysis of lactose by intestinal lactase. We then tested the hypothesis that salivary proline-rich proteins (PRPs) could modulate this inhibition and stabilize EGCG. Inhibition by EGCG of digestive enzymes (α-amylase>chymotrypsin>trypsin>lactase≫pepsin) was alleviated ∼2-6-fold by PRPs. Furthermore, PRPs appeared stable to proteolysis and also stabilized EGCG under digestive conditions in vitro. This is the first report on EGCG inhibition of lactase, and it quantifies the protective role of PRPs against EGCG inhibition of digestive enzymes.

Predicting phenolic acid absorption in Caco-2 cells: a theoretical permeability model and mechanistic study.

There is a considerable need to rationalize the membrane permeability and mechanism of transport for potential nutraceuticals. The aim of this investigation was to develop a theoretical permeability equation, based on a reported descriptive absorption model, enabling calculation of the transcellular component of absorption across Caco-2 monolayers. Published data for Caco-2 permeability of 30 drugs transported by the transcellular route were correlated with the descriptors 1-octanol/water distribution coefficient (log D, pH 7.4) and size, based on molecular mass. Nonlinear regression analysis was used to derive a set of model parameters a′, β′, and b′ with an integrated molecular mass function. The new theoretical transcellular permeability (TTP) model obtained a good fit of the published data (R2 = 0.93) and predicted reasonably well (R2 = 0.86) the experimental apparent permeability coefficient (Papp) for nine non-training set compounds reportedly transported by the transcellular route. For the first time, the TTP model was used to predict the absorption characteristics of six phenolic acids, and this original investigation was supported by in vitro Caco-2 cell mechanistic studies, which suggested that deviation of the Papp value from the predicted transcellular permeability (Papptrans) may be attributed to involvement of active uptake, efflux transporters, or paracellular flux.

Analysis of Phenolic Compounds in Portuguese Wild and Commercial Berries after Multienzyme Hydrolysis

Berry fruits are a good source of phenolic compounds and thus, potentially beneficial to health. Phenolic compounds are mainly present as a variety of conjugated forms, either with sugars via O-glycosidic bonds or with other polyols as esters. This chemodiversity makes characterization and identification highly demanding. Selected varieties of commercial blueberries, raspberries and blackberries and the two wild berries Portuguese crowberry and strawberry tree fruits were characterized for individual phenolic content by liquid chromatography-diode array detection and mass spectrometry (HPLC-DAD-MS) after hydrolysis by a novel combination of the fungal glycosidases hesperidinase and cellulase. This approach is shown to be a simple alternative to other existing methods for analysis of plant phenolic compound aglycones. The hydrolysis of glycosides and organic acid esters is efficient and less aggressive than acid and alkaline hydrolysis. This method is able to disclose new sources of dietary phenolic compounds, and the potential usefulness of Portuguese crowberry and strawberry tree fruit is herein demonstrated.

Bone mineral density, polyphenols and caffeine: a reassessment.

Several studies have shown beneficial associations between tea consumption and bone mineral density (BMD) and fracture risk. Current investigations into potential mechanisms of benefit are focused upon the F and polyphenol components of tea. However, previous studies have pointed towards caffeine consumption as a potential risk factor for low BMD and high fracture risk. Tea, therefore, represents an interesting paradox as a mildly caffeinated beverage that may enhance bone health. Fruit and vegetable intake has also been associated with BMD, and it is now apparent that several fruit and vegetable components, including polyphenols, may contribute positively to bone health. Evidence surrounding the function(s) of polyphenol-rich foods in bone health is examined, along with more recent studies challenging the relevance of caffeine consumption to in vivo Ca balance. Plant foods rich in polyphenols such as tea, fruit and vegetables, as significant factors in a healthy diet and lifestyle, may have positive roles in bone health, and the negative role of caffeine may have been overestimated. The present review covers evidence of dietary mediation in positive and negative aspects of bone health, in particular the roles of tea, fruit and vegetables, and of caffeine, flavonoids and polyphenols as components of these foods. Since the deleterious effects of caffeine appear to have been overstated, especially in respect of the positive effects of flavonoids, it is concluded that a reassessment of the role of caffeinated beverages may be necessary.

A randomized controlled trial of green tea catechins in protection against ultraviolet radiation–induced cutaneous inflammation,

Background: Safe systemic protection from the health hazards of ultraviolet radiation (UVR) in sunlight is desirable. Green tea is consumed globally and is reported to have anti-inflammatory properties, which may be mediated through the impact on cyclooxygenase and lipoxygenase pathways. Recent data suggest that green tea catechins (GTCs) reduce acute UVR effects, but human trials examining their photoprotective potential are scarce. Objective: We performed a double-blind, randomized, placebo-controlled trial to examine whether GTCs protect against clinical, histologic, and biochemical indicators of UVR-induced inflammation. Design: Healthy adults (aged 18–65 y, phototypes I–II) were randomly allocated to 1350 mg encapsulated green tea extract (540 mg GTC) with 50 mg vitamin C or placebo twice daily for 3 mo. Impact on skin erythema, dermal leukocytic infiltration, and concentrations of proinflammatory eicosanoids was assessed after solar-simulated UVR challenge, and subject compliance was determined through assay of urinary GTC metabolite epigallocatechin glucuronide. Results: Volunteers were assigned to the active (n = 25) or the placebo (n = 25) group. After supplementation, median (IQR) sunburn threshold (minimal erythema dose) was 28 (20–28) and 20 (20–28) mJ/cm2 in the active and placebo groups, respectively (nonsignificant), with no difference in AUC analysis for measured erythema index after a geometric series of 10 UVR doses. Skin immunohistochemistry showed increased neutrophil and CD3+ T-lymphocyte numbers post-UVR in both groups (P < 0.01) with no statistically significant differences between groups after supplementation. Cyclooxygenase and lipoxygenase metabolites prostaglandin E2 (vasodilator) and 12-hydroxyeicosatetraenoicacid (chemoattractant), respectively, increased after UVR (P < 0.05), with no differences between supplementation groups. Conclusion: Oral GTC (1080 mg/d) with vitamin C over 3 mo did not significantly reduce skin erythema, leukocyte infiltration, or eicosanoid response to UVR inflammatory challenge. This trial was registered at clinicaltrials.gov as NCT01032031.