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Cocoa has beneficial health effects partly due to its high flavanol content. This study was aimed at assessing the absorption and metabolism of polyphenols in two soluble cocoa products: a conventional (CC) and a flavanol-rich product (CC-PP). A crossover, randomized, blind study was performed in 13 healthy men and women. On two different days, after an overnight fast, volunteers consumed one serving of CC (15 g) or CC-PP (25 g) in 200 mL of semi-skimmed milk containing 19.80 mg and 68.25 mg of flavanols, respectively. Blood and urine samples were taken, before and after CC and CC-PP consumption, and analyzed by high-performance liquid chromatography coupled to electrospray ionisation and quadrupole time-of-flight mass spectrometry (HPLC-ESI-QToF-MS). Up to 10 and 30 metabolites were identified in plasma and urine, respectively. Phase II derivatives of epicatechin were identified with kinetics compatible with small intestine absorption, although the most abundant groups of metabolites were phase II derivatives of phenyl-γ-valerolactone and phenylvaleric acid, formed at colonic level. 5-(4′-Hydroxyphenyl)-γ-valerolactone-sulfate could be a sensitive biomarker of cocoa flavanol intake. CC and CC-PP flavanols showed a dose-dependent absorption with a recovery of 35%. In conclusion, cocoa flavanols are moderately bioavailable and extensively metabolized, mainly by the colonic microbiota.

Wine is one of the most consumed beverages around the world. It is composed of alcohols, sugars, acids, minerals, proteins and other compounds, such as organic acids and volatile and phenolic compounds (also called polyphenols). Polyphenols have been shown to be highly related to both (i) wine quality (color, flavor, and taste) and (ii) health-promoting properties (antioxidant and cardioprotective among others). Polyphenols can be grouped into two big families: (i) Flavonoids, including anthocyanidins, flavonols, flavanols, hydrolysable and condensed tannins, flavanones, flavones and chalcones; and (ii) Non-flavonoids, including hydroxycinnamic acids, hydroxybenzoic acids, stilbenes, tyrosol and hydroxytyrosol. Each group affects in some way the different properties of wine to a greater or a lesser extent. For that reason, the phenolic composition can be managed to obtain singular wines with specific, desirable characteristics. The current review presents a summary of the ways in which the phenolic composition of wine can be modulated, including (a) invariable factors such as variety, field management or climatic conditions; (b) pre-fermentative strategies such as maceration, thermovinification and pulsed electric field; (c) fermentative strategies such as the use of different yeasts and bacteria; and (d) post-fermentative strategies such as maceration, fining agents and aging. Finally, the different extraction methods and analytical techniques used for polyphenol detection and quantification have been also reviewed.

In this pre-registered study, we investigated the effects of acute cocoa flavanol (CF) consumption on cognitive control and response inhibition processes, at two different dosage levels. This crossover study was randomized, placebo-controlled, gender-balanced, and double-blind, and included 36 healthy adult participants. Participants consumed three different drinks across separate sessions: a placebo drink containing alkalized cocoa powder, a low-dose drink with 415 mg CF, and a medium-dose drink with 623 mg CF, both derived from flavanol-rich cocoa powder. Following each treatment, participants completed the Flanker, Simon, and Go/No-go tasks in a counterbalanced order. We analyzed accuracy and response times for congruent and incongruent trials in the Simon and Flanker tasks, and commission errors, omission errors, and response times in the Go/No-go task. The acute effects of CF on cognitive control and response inhibition were examined using (Generalized) Linear Mixed Model analysis, which included random intercepts, fixed effects, and random slopes. Results revealed that neither dose of CF acutely improved accuracy, interference scores, errors, or response times in these three tasks. Furthermore, neither participant gender nor BMI predicted performance in cognitive control or response inhibition beyond the effects of the treatment conditions. Taken together, these findings suggest that acute cocoa flavanol consumption has no significant effect on cognitive control or response inhibition in healthy young adults.

Plant reproduction requires long-distance growth of a pollen tube to fertilize the female gametophyte. Prior reports suggested that mutations altering synthesis of flavonoids, plant specialized metabolites that include flavonols and anthocyanins, impair pollen development in several species, but the mechanism by which flavonols enhanced fertility was not defined. Here, we used genetic approaches to demonstrate that flavonols enhanced pollen development by reducing the abundance of reactive oxygen species (ROS). We further showed that flavonols reduced high-temperature stress-induced ROS accumulation and inhibition of pollen tube growth. The anthocyanin reduced (are) tomato mutant had reduced flavonol accumulation in pollen grains and tubes. This mutant produced fewer pollen grains and had impaired pollen viability, germination, tube growth, and tube integrity, resulting in reduced seed set. Consistent with flavonols acting as ROS scavengers, are had elevated levels of ROS. The pollen viability, tube growth and integrity defects, and ROS accumulation in are were reversed by genetic complementation. Inhibition of ROS synthesis or scavenging of excess ROS with an exogenous antioxidant treatment also reversed the are phenotypes, indicating that flavonols function by reducing ROS levels. Heat stress resulted in increased ROS in pollen tubes and inhibited tube growth, with more pronounced effects in the are mutant that could be rescued by antioxidant treatment. These results are consistent with increased ROS inhibiting pollen tube growth and with flavonols preventing ROS from reaching damaging levels. These results reveal that flavonol metabolites regulate plant sexual reproduction at both normal and elevated temperatures by maintaining ROS homeostasis.

The tea plant ( Camellia sinensis ) presents an excellent system to study evolution and diversification of the numerous classes, types and variable contents of specialized metabolites. Here, we investigate the relationship among C. sinensis phylogenetic groups and specialized metabolites using transcriptomic and metabolomic data on the fresh leaves collected from 136 representative tea accessions in China. We obtain 925,854 high-quality single-nucleotide polymorphisms (SNPs) enabling the refined grouping of the sampled tea accessions into five major clades. Untargeted metabolomic analyses detect 129 and 199 annotated metabolites that are differentially accumulated in different tea groups in positive and negative ionization modes, respectively. Each phylogenetic group contains signature metabolites. In particular, CSA tea accessions are featured with high accumulation of diverse classes of flavonoid compounds, such as flavanols, flavonol mono-/di-glycosides, proanthocyanidin dimers, and phenolic acids. Our results provide insights into the genetic and metabolite diversity and are useful for accelerated tea plant breeding. The molecular basis for the unique taste and aroma of tea cultivars is largely unknown, but is critical for breeding new cultivars. Here the authors use transcriptomics and metabolomics to study the relationship among phylogenetic groups and specialized metabolites from 136 tea accessions in China.

Background/Objectives: Flavanols may provide protection against insulin resistance, but little is known about the amounts and types of flavanols that may be efficacious. Subjects/Methods: This study was designed to determine whether cocoa flavanols, over a range of intakes, improve biomarkers of glucose regulation, inflammation and hemostasis in obese adults at risk for insulin resistance. As an adjunct, green tea and cocoa flavanols were compared for their ability to modulate these biomarkers. In a randomized crossover design, 20 adults consumed a controlled diet for 5 days along with four cocoa beverages containing 30–900 mg flavanol per day, or tea matched to a cocoa beverage for monomeric flavanol content. Results: Cocoa beverages produced no significant changes in glucose, insulin, total area under the concentration–time curve (AUC) for glucose or total insulin AUC. As the dose of cocoa flavanols increased, total 8-isoprostane concentrations were lowered (linear contrast, P =0.02), as were C-reactive protein (CRP) concentrations (linear contrast, P =0.01). The relationship between cocoa flavanol levels and interleukin-6 (IL-6) concentrations was quadratic, suggesting that a maximum effective dose was achieved (quadratic contrast, P =0.01). There were no significant effects on measured indices of glucose regulation, nor on those of total 8-isoprostane, CRP and IL-6 concentrations, when cocoa and green tea were compared. However, relative to cocoa, green tea lowered fibrinogen concentrations ( P =0.0003). Conclusions: Short-term intake of cocoa and green tea flavanols does not appear to improve glucose metabolism; they do affect selected markers of one or more measures of oxidative stress, inflammation or hemostasis in obese adults at risk for insulin resistance.

Kidney fibrosis is the hallmark of chronic kidney disease (CKD) progression, whereas no effective anti-fibrotic therapies exist. Recent evidence has shown that tubular ferroptosis contributes to the pathogenesis of CKD with persistent proinflammatory and profibrotic responses. We previously reported that natural flavonol fisetin alleviated septic acute kidney injury and protected against hyperuricemic nephropathy in mice. In this study, we investigated the therapeutic effects of fisetin against fibrotic kidney disease and the underlying mechanisms. We established adenine diet-induced and unilateral ureteral obstruction (UUO)-induced CKD models in adult male mice. The two types of mice were administered fisetin (50 or 100 mg·kg −1 ·d −1 , i.g.) for 3 weeks or 7 days, respectively. At the end of the experiments, the mice were euthanized, and blood and kidneys were gathered for analyzes. We showed that fisetin administration significantly ameliorated tubular injury, inflammation, and tubulointerstitial fibrosis in the two types of CKD mice. In mouse renal tubular epithelial (TCMK-1) cells, treatment with fisetin (20 μM) significantly suppressed adenine- or TGF-β1-induced inflammatory responses and fibrogenesis, and improved cell viability. By quantitative real-time PCR analysis of ferroptosis-related genes, we demonstrated that fisetin treatment inhibited ferroptosis in the kidneys of CKD mice as well as in injured TCMK-1 cells, as evidenced by decreased ACSL4, COX2, and HMGB1, and increased GPX4. Fisetin treatment effectively restored ultrastructural abnormalities of mitochondrial morphology and restored the elevated iron, the reduced GSH and GSH/GSSG as well as the increased lipid peroxide MDA in the kidneys of CKD mice. Notably, abnormally high expression of the ferroptosis key marker ACSL4 was verified in the renal tubules of CKD patients (IgAN, MN, FSGS, LN, and DN) as well as adenine- or UUO-induced CKD mice, and in injured TCMK-1 cells. In adenine- and TGF-β1-treated TCMK-1 cells, ACSL4 knockdown inhibited tubular ferroptosis, while ACSL4 overexpression blocked the anti-ferroptotic effect of fisetin and reversed the cytoprotective, anti-inflammatory, and anti-fibrotic effects of fisetin. In summary, we reveal a novel aspect of the nephroprotective effect of fisetin, i.e. inhibiting ACSL4-mediated tubular ferroptosis against fibrotic kidney diseases.

Flavonols, representing a subclass of flavonoids, are an important group of polyphenols. Their activity is associated with a number of beneficial properties, including hepatoprotective, senolytic, neuroprotective, and anticancer properties. They are found abundantly in many fruits, vegetables, and plant products, but flavonols’ chemistry and structural properties result in their low bioavailability in vivo. In recent years, more and more studies have emerged that aim to increase the therapeutic potential of compounds belonging to this group, including by developing innovative nanoformulations. The present work focuses on the various steps, such as chemical analysis of the compounds, preformulation studies using drug delivery systems, preclinical studies, and finally clinical trials. Each of these elements is important not only for the innovation and efficacy of the therapy but most importantly for the patient’s health. There are also a limited number of studies assessing the population concentration of flavonols in the blood; therefore, this review presents an up-to-date survey of the most recent developments, using the most important compounds from the flavonol group.

Background: Sitting is highly prevalent among young and older adults and can transiently reduce cerebral blood flow. Dietary flavanols confer benefits to the peripheral vasculature and may be effective at counteracting the impact of sitting in the cerebrovasculature. The aim of this study was to investigate whether the acute ingestion of flavanols prior to sitting improves common carotid artery (CCA) blood flow/shear rate (BF/SR) in young and older individuals. Methods: Two acute randomized, double-blinded, cross-over, placebo-controlled studies were conducted in 40 healthy young males (high-fit: 22.2 ± 2.9 yr., low-fit: 23.2 ± 4.1 yr., N = 20 per group) and 20 healthy older adults (72.4 ± 5.0 yr.). Participants consumed either a high- (695 mg) or low-flavanol (5.6 mg) cocoa beverage just before a 2 h sitting bout. Resting CCA retrograde/anterograde BF and SR, as well as arterial diameter, were assessed before and after the intervention. Results: Sitting reduced anterograde BF and/or SR in young and older individuals (p < 0.001) but only resulted in increases in retrograde BF (p = 0.021) and SR (p = 0.022) in the older group. Flavanols did not affect anterograde BF/SR in either group (p > 0.05) but mitigated (non-significant interaction: p = 0.053) sitting-induced increases in retrograde BF/SR in older individuals, with retrograde BF (p = 0.028) and SR (p = 0.033) increasing significantly only after intake of the low-flavanol beverage. No changes in arterial diameter were detected. Conclusions: This suggests that flavanols may have the potential to attenuate the detrimental sitting-induced increases in retrograde BF and SR in older adults, although larger well-powered studies are required to confirm this.

PurposeCold-induced vasodilation (CIVD) is an oscillatory rise in blood flow to glabrous skin that occurs in cold-exposed extremities. Dietary flavanols increase bioavailable nitric oxide, a proposed mediator of CIVD through active vasodilation and/or withdrawal of sympathetic vascular smooth muscle tone. However, no studies have examined the effects of flavanol intake on extremity skin perfusion during cold exposure. We tested the hypothesis that acute and 8-day flavanol supplementation would augment CIVD during single-digit cold water immersion (CWI).MethodsEleven healthy adults (24 ± 6 years; 10 M/1F) ingested cocoa flavanols (900 mg/day) or caffeine- and theobromine-matched placebo for 8 days in a double-blind, randomized, crossover design. On Days 1 and 8, CIVD was assessed 2 h post-treatment. Subjects immersed their 3rd finger in warm water (42 °C) for 15 min before CWI (4 °C) for 30 min, during which nail bed and finger pad skin temperature were measured.ResultsFlavanol ingestion had no effect on CIVD frequency (Day 1, Flavanol: 3 ± 2 vs. Placebo: 3 ± 2; Day 8, Flavanol: 3 ± 2 vs. Placebo: 3 ± 1) or amplitude (Day 1, Flavanol: 4.3 ± 1.7 vs. Placebo: 4.9 ± 2.6 °C; Day 8, Flavanol: 3.9 ± 1.9 vs. Placebo: 3.9 ± 2.0 °C) in the finger pad following acute or 8-day supplementation (P > 0.05). Furthermore, average, nadir, and apex finger pad temperatures during CWI were not different between treatments on Days 1 or 8 of supplementation (P > 0.05). Similarly, no differences in CIVD parameters were observed in the nail bed following supplementation (P > 0.05).ConclusionThese data suggest that cocoa flavanol ingestion does not alter finger CIVD.Clinical Trial Registration Clinicaltrials.gov Identifier: NCT04359082. April 24, 2020.