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Background: Osteoarthritis (OA), a prevalent joint disease, causes immense suffering to thousands of patients, impairing their mobility and diminishing their quality of life. Current treatment methods primarily rely on analgesics or anti-inflammatory drugs to alleviate symptoms but fail to achieve the desired therapeutic outcome., Methods: To better realize therapeutic effects of OA, procyanidins (PAs), as a type of plant flavonoids with strong antioxidant and anti-inflammatory activities, were designed to self-assembly with well-dispersible Pluronic F127 (PF127) through the hydrogen-bond interaction to present an injectable, biocompatibility PA nanospheres., Results: These nanospheres significantly increased the cell viability in mouse L929 fibroblasts and ADTC5 chondrocytes compared with unassembled PAs. In addition, the self-assembling PAs/PF127 nanospheres enhanced the protein expression of collagen (COL1A1 and COL3A1) in fibroblasts, and the expression of glycosaminoglycan and COL2A1 was also higher than unassembled PAs in chondrocytes, this heralded the potential to achieve OA repair strategies at the cellular level. In an enzymolysis model of rat OA, PAs/PF127 nanospheres significantly reduce joint space swelling in the early stages of cartilage destruction and accelerate the formation of subchondral bone and cartilaginous surface., Implication: This study offers valuable insights into the preparation of novel PA nanospheres for effective repair of OA., Competing Interests: The authors declare no competing financial interest., (© 2025 Li et al.)

Procyanidins (PCs), a kind of polyphenolic compound, have attracted extensive attention due to their strong antioxidant, anti-inflammatory and other activities. However, PCs are susceptible to complex micro-environments, resulting in low stability, poor target tissue delivery and bioavailability, which limits their biological effects. Therefore, it is urgent to find some suitable pathways to protect PCs, avoid their degradation, and maximize their health benefits in nutritional intervention. This review focused on the design and construction of different types of bio-based delivery systems loaded with PCs, such as nanoparticles, microparticles, emulsions, liposomes, hydrogels and fibers. The advantages and biological effects of PCs-based delivery systems in promoting cellular uptake, realizing targeted release of organs, cells and organelles, and even nutritional intervention for different chronic diseases were summarized. Furthermore, the development prospects and challenges of delivery systems in the field of precision nutrition were discussed. The construction of these delivery systems can effectively improve the stability and bioavailability of PCs, and maximize their precise nutritional intervention for various chronic diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Scope: The absorption, disposition, metabolism, and excretion (ADME) of phenolic compounds are key factors in determining their bioactivity. The group demonstrates that the ADME of a Grape Seed Proanthocyanidin Extract (GSPE) depends on sex in adult rats and specifically, methylated metabolites are only quantified in brain male adult rats. The aim of this study is to determine whether these differences exist before puberty., Methods and Results: Prepubescent 4-week-old male and female Wistar rats are administered GSPE at a dose of 1000 mg kg -1 . Plasma, liver, mesenteric white adipose tissue (MWAT), brain, and kidneys are extracted excised 2 h after GSPE administration, and the PAs metabolite profile is studied by HPLC-ESI-MS/MS. Moreover, plasma estradiol and brain and liver catechol-O-methyltransferase (COMT) protein levels are also studied. Results showed that there are no differences in plasma and brain among sexes and only differences are observed in liver, MWAT, and kidney with individual metabolites. This agrees with the lack of differences in estradiol and COMT levels among sexes. However, the ADME of PAs metabolites is higher in male rats., Conclusions: The results demonstrate lack of sex-dependence in metabolite profile in prepubescent rats, suggesting that sex differences in the metabolism of GSPE occur due to puberty., (© 2024 The Author(s). Molecular Nutrition & Food Research published by Wiley‐VCH GmbH.)

The bioaccessibility of tannins as antioxidants in meat is essential to maximise their effectiveness in protecting the product. This property determines the amount of tannins available to interact with meat components, inhibiting lipid and protein oxidation and, consequently, prolonging shelf life and preserving the sensory quality of the product. The objective of this study was to evaluate the bioaccessibility of condensed tannins (CT) from Acacia mearnsii extract (AME) and their effect on the physico-chemical characteristics of fattened lamb meat. Thirty-six Dorset × Hampshire lambs (3 months old and 20.8 ± 3.3 kg live weight) were used. The lambs were distributed equally ( n  = 9) into four treatments: T1, T2, T3 and T4, which included a basal diet plus 0%, 0.25%, 0.5% and 0.75% of CT from AME, respectively. At the end of the fattening period, bioaccessibility was evaluated, the animals were slaughtered and a sample of the longissimus dorsi (LD) muscle was collected to assess colour, lipid oxidation, cooking weight loss and shear force on days 1, 4, 7 and 14 of shelf-life, in samples preserved at -20 °C. In addition, the long chain fatty acid profile was analysed. A completely randomised design was used, and the means were compared with Tukey's test ( P  < 0.05). The mean lightness (L*), yellowness (b*) and hue (H*) values were higher for T3 and T4. The addition of CT did not affect ( P  > 0.05) redness (a*), cooking weight loss (CWL) or shear force (SF). T4 decreased ( P  < 0.05) stearic acid and increased cis-9 trans-12 conjugated linoleic acid (CLA). Bioaccessibility was higher in the supplemented groups (T1 < T2, T3 and T4). In conclusion, supplementing CT from AME in the diet of lambs did not reduce lipid oxidation, but T3 or T4 improved some aspects of meat colour and CLA deposition., Competing Interests: The authors declare there are no competing interests., (©2024 García Salas et al.)

W/O/W emulsions were easily prepared by oleogelation of the oil phase using rice bran wax (RBX) and their microstructure, stability, rheology and protection of proanthocyanidins and β-carotene were investigated. Formation of the W/O/W emulsion was confirmed using confocal laser scanning microscopy and staining of the inner aqueous phase by tartrazine. The average particle size and viscosity of the emulsion increased as the RBX concentration increased. Moreover, RBX increased the stability of the emulsion and the emulsion was the most stable when the RBX concentration was 8.0% or 10.0%. On the other hand, the W/O/W emulsions were used to simultaneously encapsulate proanthocyanidins and β-carotene. Specifically, proanthocyanidins and β-carotene in RBX-containing emulsions were more stable and had higher bioaccessibility than in the emulsion without RBX. Besides, both their chemical stability and bioaccessibility reached the maximum value when the RBX concentration was 8.0% or 10.0%. In summary, the optimal RBX concentration was 8.0%., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Whey proteins and oligomeric proanthocyanidins have nutritional value and are widely used in combination as food supplements. However, the effect of the interactions between proanthocyanidins and whey proteins on their stability has not been studied in depth. In this work, we aimed to characterize the interactions between β-Lactoglobulin (β-LG) and α-lactalbumin (α-LA) and oligomeric proanthocyanidins, including A1, A2, B1, B2, B3, and C1, using multi-spectroscopic and molecular docking methods. Fluorescence spectroscopic data revealed that all of the oligomeric proanthocyanidins quenched the intrinsic fluorescence of β-LG or α-LA by binding-related fluorescence quenching. Among the six oligomeric proanthocyanidins, A1 showed the strongest affinity for β-LG (K a = 2.951 (±0.447) × 10 4 L∙mol -1 ) and α-LA (K a = 1.472 (±0.236) × 10 5 L∙mol -1 ) at 297 K. β-LG/α-LA and proanthocyanidins can spontaneously form complexes, which are mainly induced by hydrophobic interactions, hydrogen bonds, and van der Waals forces. Fourier-transform infrared spectroscopy (FTIR) and circular dichroism spectroscopy showed that the secondary structures of the proteins were rearranged after binding to oligomeric proanthocyanidins. During in vitro gastrointestinal digestion, the recovery rate of A1 and A2 increased with the addition of WPI by 11.90% and 38.43%, respectively. The addition of WPI (molar ratio of 1:1) increased the retention rate of proanthocyanidins A1, A2, B1, B2, B3, and C1 during storage at room temperature by 14.01%, 23.14%, 30.09%, 62.67%, 47.92%, and 60.56%, respectively. These results are helpful for the promotion of protein-proanthocyanidin complexes as functional food ingredients in the food industry.

Scope: The majority of ingested flavanols reach the colon where they are catabolized by the microbiota to form hydroxyphenyl-γ-valerolactones (HGVLs). It is not known if the HGVLs are catabolic products of monomeric (epi)catechins (EPC), oligomeric procyanidins (OPCs), or both. Using data from a randomized, double-blind, placebo-controlled crossover trial the relative contributions of catechins and OPC to the bioavailable pool of HGVLs are estimated., Methods and Results: Participants ingested an apple extract once daily for 28 days that delivered the following: i) 70 mg EPC and 65 mg OPC (low dose EPC), ii) 140 mg EPC and 130 mg OPC (high dose EPC), iii) 6 mg EPC and 130 mg OPC (OPC), and iv) a placebo control. Urine is collected over a 24-h period before and after treatments. The median urinary excretion of HGVLs after ingestion of the high dose EPC is tenfold higher than that excreted after ingestion of the OPC that provided an equivalent dose of PC. Approximately 22% of catechins are converted to HGVLs in contrast to PC, for which there is limited conversion., Conclusion: Monomeric catechins are efficiently converted to derived HGVLs that are absorbed and excreted in human urine, whereas oligomeric PCs are much less efficiently converted., (© 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This study assessed the phenolics and their bioaccessibility through an in vitro digestion system coupled to a simulated intestinal barrier in eight edible flowers of distinct colors, namely mini rose, torenia, mini daisy, clitoria, cosmos, cravine, begonia and tagete. The antioxidant activity of the flowers before in vitro digestion, in their derived dialyzed and non-dialyzed fractions was evaluated using distinct approaches. All flowers presented in their composition phenolic acids, stilbenes, flavanol, anthocyanin, flavonol and flavanone, however distinct compounds and contents were found in each flower. The bioaccessibility varied among the phenolics and within the flower source (p < 0.05). Cosmos presented the highest (p < 0.05) content of phenolics and activity in ORAC assay before in vitro digestion and in dialyzed and non-dialyzed fraction; the observed activity was correlated (r = 0.9) to its major compounds, hesperidin and rutin, as well as to caftaric acid and procyanidin B2. Mini rose displayed the highest antioxidant activity in FRAP and DPPH assays before in vitro digestion; its dialyzed and non-dialyzed fraction showed the highest activity in FRAP, correlated to pelargonidin 3,5-diglucoside, catechin, epicatechin galate, epicagocatechin galate, procyanidin A2, quercitin 3-glucoside and trans-resveratrol (r = 0.9). In DPPH assay, mini rose showed the highest activity in the non-dialyzed fraction, while cravine showed the highest activity in the dialyzed fraction, which was mainly correlated to syringic acid (r = 1.0), pelargonidin 3,5-diglucoside and epicatechin (r = 0.9). Results show great variability in the phenolic composition and their bioaccessibility among the edible flowers studied. Our findings indicate cosmos and mini rose as sources of bioaccessible phenolics with great antioxidant activity., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In this paper, the Dynamic Gastrointestinal Simulator (simgi®) is used as a model to the study the metabolic activity of probiotics at the intestinal level, and in particular, to assess the impact of probiotic supplementation in the microbial metabolism of grape polyphenols. Two independent simulations using fecal samples from two healthy volunteers were carried out. Changes in microbiota composition and in metabolic activity were assessed by qPCR and 16S rRNA gene sequencing and by analyses of phenolic metabolites and ammonium ions (NH 4 + ). The strain Lactobacillus plantarum CLC 17 was successfully implanted in the colon compartments of the simgi® after daily feeding of 2 × 10 10 CFU/day for 7 days. Overall, no changes in bacterial diversity were observed after probiotic implantation. In comparison to the digestion of the grape polyphenols on their own, the inclusion of L. plantarum CLC 17 in the simgi® colon compartments led to a greater formation of phenolic metabolites such as benzoic acids, probably by the breakdown of high-molecular-weight procyanidin polymers. These results provide evidence that the probiotic strain Lactobacillus plantarum CLC 17 may improve the metabolism of dietary polyphenols when used as a food ingredient., Competing Interests: Declaration of Competing Interest We declare that we have no conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Studying bioavailability of polyphenols is essential to understand the health effects of these compounds. Human epithelial cells are commonly used in intestinal absorption and transport experiments but the changes polyphenols undergo during incubation, due to their chemical instability under the cell culture conditions, are scarcely known and might lead to inaccurate conclusions. Based on abundance of flavanols and hydroxycinnamic acids in the diet, epicatechin, epicatechin-3-gallate and procyanidin B2 as flavanols along with 5-caffeoylquinic and 3,5-dicaffeoylquinic acids as hydroxycinnamic acids were selected to comparatively evaluate their absorption and metabolism using an in vitro Caco-2 cell model. Special emphasis was paid to the structure-stability relationship of these phenolic compounds in Dulbecco's Modified Eagle's Medium (DMEM) under the cell culture conditions. The tested compounds were scarcely absorbed and minimally metabolized by the intestinal epithelium cells. The cell transport study showed prevalent efflux for flavanols opposite to absorption for hydroxycinnamates. Intestinal metabolism revealed that hydroxycinnamates were preferentially hydrolyzed and subsequently methylated, whereas hydrolysis of flavanols could not be confirmed, being mostly conjugated to sulfate, methyl- and methyl-sulfate derivatives. It is noteworthy that methyl derivatives of procyanidin-B2 were detected inside Caco-2 cells, confirming its absorption. In addition, culture medium influenced phenol isomerization to a higher extent than cells. In conclusion, hydroxycinnamates were better absorbed than flavanols although their bioavailability was limited in this intestinal cell model., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Proanthocyanidins (PAs) are a group of polyphenols enriched in plant and human food. In recent decades, epidemiological studies have upheld the direct relationship between PA consumption and health benefits; therefore, studies on PAs have become a research hotspot. Although the oral bioavailability of PAs is quite low, pharmacokinetics data revealed that some small molecules and colonic microbial metabolites of PAs could be absorbed and exert their health beneficial effects. The pharmacological effects of PAs mainly include anti-oxidant, anticancer, anti-inflammation, antimicrobial, cardiovascular protection, neuroprotection, and metabolism-regulation behaviors. Moreover, current toxicological studies show that PAs have no observable toxicity to humans. This review summarizes the resources, extraction, structures, pharmacokinetics, pharmacology, and toxicology of PAs and discusses the limitations of current studies. Areas for further research are also proposed.

The low solubility, instability, and low bioavailability of food bioactive compounds such as polyphenols and flavonoids, restrict their applications in the fields of food science and nutrition. Ferritin protein has received more and more attention in encapsulation and delivery of the bioactive compounds due to its nanosized shell-like structure and its reversible self-assembly character. After encapsulation, bioactive compounds can be functionalized by the ferritin vehicle to achieve stabilization, solubilization, and targeted delivery. In addition, the outer interfaces and the porous structure of ferritin are also artfully harnessed for encapsulation. This review focuses on the newest advances in the fabrication, characterization, and application of ferritin-based nano-carriers for bioactive compounds by the reversible self-assembly, outer-interface decoration methods, and the channel-directed approach. The functional improvements of food bioactive compounds, including their solubility, stability, and cellular uptake, are emphasized. The limitations that affect ferritin encapsulation are also examined., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The health-promoting functions of fruit phenolic compounds are mainly attributed to their metabolites. The organic cultivation of fruits is becoming increasingly popular. Thus, this study evaluates whether the differences in red Grenache grapes derived from organic culture conditions influence the bioavailability and metabolism of phenolic compounds in rats. Organic and nonorganic (conventional) red Grenache grapes (OG and CG, respectively) were characterized and administered to Wistar rats (65 mg gallic acid equivalents/kg bw). Serum was recollected at different time points, and the phenolic metabolites were quantified by HPLC-ESI-MS/MS. The results showed that organic cultivation increased the oligomeric proanthocyanidin and anthocyanidin contents and decreased the content of free flavanols and dietary fiber. The serum profile of OG-administered rats showed higher metabolite concentrations at 2 h and reduced metabolite concentration at 24 h compared with the CG-administered rats. Thus, this particular serum kinetic behavior might influence the bioactivity of their phenolic compounds., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The ultimate health benefits of peanuts and tree nuts partially depend on the effective gastrointestinal delivery of their phytochemicals. The chemical composition and in vitro bioaccessibility of tocopherols, tocotrienols and phenolic compounds from peanuts and seven tree nuts were evaluated by analytical and chemometric methods. Total fat and dietary fiber (g 100 g -1 ) ranged from 34.2 (Emory oak acorn) to 72.5 (pink pine nut; PPN) and from 1.2 (PPN) to 22.5 (pistachio). Samples were rich in oleic and linoleic acids (56-87 g 100 g -1 oil). Tocopherols and tocotrienols (mg·kg -1 ) ranged from 48.1 (peanut) to 156.3 (almond) and 0 (almond, pecan) to 22.1 (PPN) and hydrophilic phenolics from 533 (PPN) to 12,896 (Emory oak acorn); flavonoids and condensed tannins (mg CE.100 g -1 ) ranged from 142 (white pine nut) to 1833 (Emory oak acorn) and 14 (PPN) to 460 (Emory oak acorn). Three principal components explained 90% of the variance associated with the diversity of antioxidant phytochemicals in samples. In vitro bioaccessibility of tocopherols, tocotrienols, hydrophilic phenolics, flavonoids, and condensed tannins ranged from 11-51%, 16-79%, 25-55%, 0-100%, and 0-94%, respectively. Multiple regression analyses revealed a potential influence of dietary fiber, fats and/or unsaturated fatty acids on phytochemical bioaccessibility, in a structure-specific manner.

Reducing starch digestibility can significantly benefit efforts to combat obesity and associated chronic diseases. Polymeric proanthocyanidins (PA) form complexes with starch via unknown mechanisms, resulting in dramatically decreased starch digestibility. We hypothesized that V-type complexes are involved in these interactions. Sorghum derived PA was complexed with amylose, amylopectin, and granular maize starches in regular and deuterated solvents, and structural properties and in vitro digestibility of the complexes investigated. Based on iodine binding, X-ray diffraction patterns, crystallinity, and thermal properties, we demonstrated, for the first time, that type II semi-crystalline V-complexes are formed between amylose and PA. Furthermore, suppression of H-bonding led to amorphous complexes, suggesting extensive H-bonding facilitate and/or stabilize the V-complexes. We speculate that the complexation involves inclusion of B-rings of the PA units into the amylose helical cavity. The V-complex formation significantly increased resistant starch in gelatinized normal starch and pure amylose (by 35-45%), indicating likely physiological benefits., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Small unilamellar and multilayered liposomes loaded with polymeric (epi)catechins up to pentamers were produced. The bioaccessibility, kinetic release profile, and degradation under in vitro gastrointestinal conditions were monitored by UHPLC-DAD-QTOF-MS/MS. The results show that all of the procyanidins underwent depolymerization and epimerization into small molecular oligomers and mainly to (epi)catechin subunits. Moreover, all of the liposome formulations presented higher bioaccessibility and antioxidant activity in comparison to their respective counterparts in non-encapsulated form. Similar results were obtained with procyanidins from cocoa extract-loaded liposomes. Namely, the bioaccessibility of dimer, trimer, and tetramer fractions from cocoa-loaded liposomes were 4.5-, 2.1-, and 9.3-fold higher than those from the non-encapsulated cocoa extract. Overall, the procyanidin release profile was dependent on their chemical structure and physicochemical interaction with the lipid carrier. These results confirmed that liposomes are efficient carriers to stabilize and transport procyanidins with the aim of enhancing their bioaccessibility at a controlled release rate.

The bioaccessibility of phenolics and antioxidant activity were determined in açaí, cupuaçu, blackberry, blueberry, jabuticaba, raspberry, cajá and soursop frozen pulps (FPs) using a digestion model coupled with a simulated intestinal barrier. Cyanidin 3-glucoside (6.56%) and pelargonidin 3-glucoside (28.33%) were bioaccessible in blueberry and raspberry. Catechin had the highest bioaccessibility in blueberry (270.71%), blackberry (137.51%), and jabuticaba (99.52%), while the highest bioaccessibility of epicatechin (153.59%) and syringic acid (147.14%) was observed in blueberry. Procyanidin B1 presented the highest bioaccessibility in cajá (102.79%) and blackberry (87.62%) and contributed to the high DPPH ▪ scavenging activity observed in these FPs. The bioaccessible fraction in soursop consisted of caffeic (8.18%), p-coumaric (7.36%), caftaric (7.96%) and chlorogenic (11.08%) acids, and these acids were correlated with the iron reduction capacity of this FP. Our study assessed the bioaccessible phenolics in several FPs and showed that those found in cajá and blackberry possesses the highest antioxidant activity., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This study investigated the possible enhancement of berberine's (BB) hypoglycemic activity by oligomeric proanthocyanidins (OPCs) and its underlying mechanism. The hypoglycemic activity of the studied compounds was evaluated in diabetic db / db mice. The cellular uptake and efflux of BB with or without OPCs were investigated using Caco-2 intestinal cells. A pharmacokinetic study of BB and OPCs was performed in Sprague Dawley (SD) mice by oral administration of the study compounds. Liquid chromatography⁻tandem mass spectrometry (LC⁻MS/MS) was employed to determine the cellular efflux, retention, and the serum concentrations of the compounds. The results revealed that OPCs considerably potentiated the hypoglycemic efficacy of BB in diabetic db / db mice. In the in vitro experiments, OPCs significantly inhibited the efflux and increased the uptake of the P-glycoprotein (P-gp) substrate rhodamine-123 (R123) and BB in Caco-2 intestinal cells. Moreover, OPCs substantially reduced the expression of P-gp in Caco-2 cells. The inhibition of BB efflux by OPCs was translated into the improved pharmacokinetics in vivo. When co-administered, OPCs obviously increased the average maximum concentration of BB in mice. In summary, this study demonstrated that combination of BB with OPCs could significantly improve the pharmacokinetics and hypoglycemic efficacy of BB, which is valuable for future exploration of the combination of BB and OPCs as oral hypoglycemic agents.

Scope: Several studies have demonstrated that flavan-3-ol/procyanidins are associated with biological functions in the prevention of various chronic diseases, including obesity and diabetes. Knowledge of their mechanisms, including bioavailability, has significantly progressed in the last decade. However, the differences of the metabolic signatures among flavan-3-ol/procyanidins remain ambiguous., Methods and Results: The metabolites in urine over time after acute administration of three typical flavan-3-ol/procyanidins ((epi)catechin [EPC], epigallocatechin gallate [EGCG], and procyanidin dimer [PC]) in view of the chemical structure were analyzed by HPLC-quadrupole TOF/MS. Several bile acid and amino acid derivatives including tryptophan and tyrosine, as well as flavan-3-ol/procyanidin conjugates and phenolic acid degradation products generated by the gut microbiota were observed in rat urine., Conclusion: Multivariate statistical analyses suggest that the exogenous and endogenous metabolites of flavan-3-ol/procyanidins greatly differ, although the chemical structures of three typical flavan-3-ol/procyanidins-EPC, EGCG, and PC-are similar. Thus, metabolomic differences likely affect their biological functions and health benefits., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: Over the past three decades, numerous studies have focused on the biological activities of oligomeric proanthocyanidins (OPCs) in the prevention of many diseases such as neurodegeneration, atherosclerosis, tumorigenesis, and microbial infections. OPC has redox-active metabolites which could modulate the intracellular redox equilibrium to maintain the antioxidant homeostasis. This redox-modulating efficiency of OPC could provide new insights into therapeutic approaches that could reduce the burden of cardiovascular diseases. The main objective of this study was to explore the biological and metabolic activities of OPC using in silico approaches., Methods: To validate the above objective, chemoinformatic tools were used to predict the metabolism of OPC after ingestion, based on both the ligand and structure of the constituent compounds., Results: OPC showed possible sites for Phase I metabolism by cytochrome P450, and the metabolites obtained thereafter may be responsible for its biological activities. Absorption, distribution, metabolism, elimination, and toxicity properties showed efficient absorption, distribution, and metabolism of OPC, without toxicity., Conclusion: Thus, from the results obtained, OPC could be strongly recommended as a cardioprotective drug., Competing Interests: There are no conflicts of interest.

The stability and bioaccessibility of polyphenol from Acacia mearnsii bark were measured at various stages during in vitro simulated digestion. Subsequently, the changes in the total polyphenol content (TPC) and biological activity were studied. The results showed that the phenolic compounds from A. mearnsii remained stable, and TPC underwent few changes during gastric digestion. Nonetheless, intestinal digestion led to the degradation of proanthocyanidins (PAs) and a significant decrease in TPC (26%). Degradation was determined by normal-phase HPLC and gel permeation chromatography. Only monomers, dimers, and trimers of flavan-3-ols were identified in the serum-accessible fraction for characterization of their bioaccessibility. The results also indicated the obvious antioxidant capacity of PAs from A. mearnsii bark, and ~53% of the α-glucosidase⁻inhibitory effect was preserved. All these findings show that PAs from A. mearnsii bark as a native plant source may be particularly beneficial for human health as a natural nutritional supplement.

The absorption and antioxidant activity of polyphenols from grape pomace (GP) are important aspects of its valorization as a feed additive in the diet of weaned piglets. This study aimed to evaluate the presence of polyphenols from GP both in vitro in IPEC cells and in vivo in the duodenum and colon of piglets fed with diets containing or not 5% GP and also to compare and correlate the aspects of their in vitro and in vivo absorption. Total polyphenolic content (TPC) and antioxidant status (TAS, CAT, SOD and GPx enzyme activity, and lipid peroxidation-TBARS level) were assessed in duodenum and colon of piglets fed or not a diet with 5% GP. The results of UV-Vis spectroscopy demonstrated that in cellular and extracellular medium the GP polyphenols were oxidized (between &lambda;max = 276 nm and &lambda;max = 627.0 nm) with the formation of o -quinones and dimers. LC-MS analysis indicated a procyanidin trimer possibly C2, and a procyanidin dimer as the major polyphenols identified in GP, 12.8% of the procyanidin trimer and 23% of the procyanidin dimer respectively being also found in the compound feed. Procyanidin trimer C2 is the compound accumulated in duodenum, 73% of it being found in the colon of control piglets, and 62.5% in the colon of GP piglets. Correlations exist between the in vitro and in vivo investigations regarding the qualitative evaluation of GP polyphenols in the cells (&lambda;max at 287.1 nm) and in the gut (&lambda;max at 287.5 nm), as oxidated metabolic products. Beside the presence of polyphenols metabolites this study shows also the presence of the unmetabolized procyanidin trimers in duodenum and colon tissue, an important point in evaluating the benefic actions of these molecules at intestinal level. Moreover the in vivo study shows that a 5% GP in piglet&rsquo;s diet increased the total antioxidant status (TAS) and decreased lipid peroxidantion (TBARS) in both duodenum and colon, and increased SOD activity in duodenum and CAT and GPx activity in colon. These parameters are modulated by the different polyphenols absorbed, mainly by the procyanidin trimers and catechin on one side and the polyphenols metabolites on the other side.

Proanthocyanidins (PAs) have several bioactivities, but they are unstable in the digestive tract and possess low bioavailability. Nanoencapsulation stabilizes these compounds for oral administration. The intestinal absorption of grape seed and skin extracts, and the poly-lactic acid (PLA) nanoparticles loaded with such extracts was modeled, taking into consideration physicochemical process parameters, evaluating the PAs concentration profile in the human small intestine. Density (ρ), solubility, viscosity (μ), diffusion coefficient (D), and the global mass transfer coefficient (K) for both substrates were estimated, simulating their passing from the intestine into the blood at 37°C. For the seed and skin extracts encapsulated in PLA the physicochemical parameters were: D = 1.81 × 10^ -5 and D = 5.72 × 10^ -5  cm 2 /s; K = 3.4 × 10^ -3 and K = 2.47 × 10^ -4  cm/s, respectively. Lower resistance was offered by the seed extract than by skin extracts (nanoencapsulated), which was explained by differences in structural composition, and average molecular weight of the two kinds of extracts, which should be more favorable to the mass transfer in comparison to the raw extracts. The concentration profile of grape extracts in the small intestine was modeled through a pure convection model, and the encapsulated extract on PLA nanoparticles using a mixed regime model, which described the process of dissolution and absorption of the grape extracts from the intestine to the blood stream. The absorbed fraction predicted by the model was 42.7 and 24.2% for seed and skin extracts, respectively. Those values increased to 100% for both extracts after the simulation with the nanoencapsulated extracts. Consequently, extract encapsulation should produce a significant increase in intestinal absorption.

Proanthocyanidins are a major group of flavonoids in the human diet, known for their strong antioxidant properties. Emerging evidence from clinical studies indicates a role of proanthocyanidins in modulating glucose homeostasis, and higher proanthocyanidin intake has been associated with reduced risk of diabetes. On the other hand, recent studies report limited bioavailability of proanthocyanidins. At relatively low concentrations in the systemic circulation, proanthocyanidins may act as cell-signaling molecules to modulate glucose homeostasis. For example, they affect hepatic glucose production via adenosine monophosphate-activated protein kinase and/or insulin-signaling pathways. There is also evidence for a direct role of proanthocyanidins in modulating several pancreatic β-cell functions: prevention of oxidative stress, enhancement of insulin secretion, and promotion of β-cell survival. Therefore, greater understanding of the potentially beneficial effects of proanthocyanidins on cell-signaling pathways implicated in glucose homeostasis is needed. In addition, further investigation to address the in vivo metabolism of proanthocyanidins and the comparative effectiveness of proanthocyanidin-derived metabolites is warranted. The dosage and the experimental model should be given special attention when results from mechanistic studies using proanthocyanidins are interpreted., (© The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Proanthocyanidins (PACs) are plant-derived, multifunctional compounds that possess high interactivity with extracellular matrix (ECM) components. The documented affinity of PACs for type-I collagen is directly correlated with their structural features and degree of polymerization. In this investigation, centrifugal partition chromatography (CPC) was used to sequentially deplete less active monomeric and polymeric PACs from a crude Pinus massoniana bark extract to create refined mixtures enriched in oligomeric PACs. The ability of these oligomeric PACs to modify the mechanical properties of the dentin collagen matrix and their biocompatibility with dental pulp cells (DPCs) was evaluated in an innovative biomimetic environment. The refined mixtures displayed high interactivity with dentin collagen as demonstrated by a significant increase (>5-fold) in the modulus of elasticity of the dentin matrix. In a simplified model of the dentin-DPC complex, DPCs embedded within their native ECM in the presence of PAC-treated dentin exhibited increased proliferation. Quantitative gene expression analyses indicated that exposure to PAC-treated dentin increased the expression of key biomineralization and odontogenic differentiation regulators, including RUNX2, BMP2, OCN, and DSPP. LC-MS/MS analysis revealed that PACs two to four units long (dimers, trimers, and tetramers) were being released from dentin into media, influencing cell behavior. Overall, the results suggested that PAC dimers, trimers, and tetramers are not only biocompatible, but enhance the differentiation of DPCs towards a phenotype that favors biomineralization. PAC-enriched refined mixtures can influence the field of biomaterials and regeneration by serving as renewable, non-cytotoxic agents that can increase the mechanical properties of biomaterials., Statement of Significance: Pine bark extract is a renewable source of structurally diverse proanthocyanidins (PACs), multifunctional compounds whose interaction with collagen can be tailored to specific purposes by enrichment of selected PACs from the complex mixture. Oligomeric PACs were enriched from the extract and were shown here to sustain desired tissue modification and were thus assessed for cellular response in a model of the dentin-pulp interface. This model was developed to mimic leaching of potentially reactive compounds into pulp tissue. Dental pulp cells exposed to PAC-treated dentin showed increased proliferation and expression of genes necessary for extracellular matrix deposition and biomineralization, processes crucial for forming new dentin. Thus, collagen-interactive PACs may also enhance tissue regeneration and have broad impact in tissue engineering., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Tannins are a heterogeneous group of high MW, water-soluble, polyphenolic compounds, naturally present in cereals, leguminous seeds and, predominantly, in many fruits and vegetables, where they provide protection against a wide range of biotic and abiotic stressors. Tannins exert several pharmacological effects, including antioxidant and free radical scavenging activity as well as antimicrobial, anti-cancer, anti-nutritional and cardio-protective properties. They also seem to exert beneficial effects on metabolic disorders and prevent the onset of several oxidative stress-related diseases. Although the bioavailability and pharmacokinetic data for these phytochemicals are still sparse, gut absorption of these compounds seems to be inversely correlated with the degree of polymerization. Further studies are mandatory to better clarify how these molecules and their metabolites are able to cross the intestinal barrier in order to exert their biological properties. This review summarizes the current literature on tannins, focusing on the main, recently proposed mechanisms of action that underlie their pharmacological and disease-prevention properties, as well as their bioavailability, safety and toxicology., Linked Articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc., (© 2016 The British Pharmacological Society.)

The bioavailability of A-type procyanidins in vivo has been rarely investigated; as such, this study discusses the effect of A-type linkage and degree of polymerization on the metabolism of procyanidins extracted from litchi pericarp (LPOPC). Sprague-Dawley rats were gavaged with (-)-epicatechin (EC) and LPOPC and sacrificed at different time points after ingestion. A-type linkage procyanidin oligomers inhibited the absorption of EC. Analysis of urinary contents from rats administered with EC, A-type procyanidin dimer (A-2), and A-type procyanidin trimer (A-3) showed distinct native and metabolite profiles for each rat. Rats fed with A-2 and A-3 presented significantly higher levels of shikimic acid and less amount of m(p)-coumaric acid metabolites in vivo and provide insight into the quantitative structure-activity relationship of procyanidin oligomers during metabolism, indicating that procyanidins with A-type linkage could induce an altered metabolic pathway of oligomers in the gastrointestinal system.

Condensed tannins' (CTs) fate along the digestive tract of ruminants may account for the variable efficacy of CTs against gastrointestinal nematodes. We analyzed CTs in the digesta of cattle fed sainfoin. With the acetone-butanol-HCl assay, the total CTs concentrations in the digesta were close to those in the diets (6.3 and 1.5% of DM in experiments 1 and 2, respectively); thus, CTs remained potentially largely undegraded/unabsorbed. With the thiolysis assay, CTs concentration was much higher in the abomasum (2.3% of DM; expt 1) compared with the rumen and intestines, along with higher mean size and prodelphinidins percentage, corroborating CTs efficacy reported only against Ostertagia ostertagi in the abomasum. In expt 2, the dietary levels of CTs were probably too low to demonstrate anthelmintic effects in the rumen. Overall, the level of CTs accessible to thiolysis is favored under the acidic conditions of the abomasum, which seems critical for anthelmintic activity.

Proanthocyanidins (PACs) are an abundant but complex class of polyphenols found in foods and botanicals. PACs are polymeric flavanols with a variety of linkages and subunits. Connectivity and degree of polymerization (DP) determine PAC bioavailability and bioactivity. Current quantitative and qualitative methods may ignore a large percentage of dietary PACs. Subsequent correlations between intake and activity are hindered by a lack of understanding of the true PAC complexity in many foods. Additionally, estimates of dietary intakes are likely inaccurate, as nutrient databank values are largely based on standards from cocoa (monomers to decamers) and blueberries (mean DP of 36). Improved analytical methodologies are needed to increase our understanding of the biological roles of these complex compounds.

Insulin resistance and abdominal obesity are present in the majority of people with the metabolic syndrome. Antioxidant therapy might be a useful strategy for type 2 diabetes and other insulin-resistant states. The combination of vitamin C (Vc) and vitamin E has synthetic scavenging effect on free radicals and inhibition effect on lipid peroxidation. However, there are few studies about how to define the best combination of more than three anti-oxidants as it is difficult or impossible to test the anti-oxidant effect of the combination of every concentration of each ingredient experimentally. Here we present a math model, which is based on the classical Hill equation to determine the best combination, called Fixed Dose Combination (FDC), of several natural anti-oxidants, including Vc, green tea polyphenols (GTP) and grape seed extract proanthocyanidin (GSEP). Then we investigated the effects of FDC on oxidative stress, blood glucose and serum lipid levels in cultured 3T3-L1 adipocytes, high fat diet (HFD)-fed rats which serve as obesity model, and KK-ay mice as diabetic model. The level of serum malondialdehyde (MDA) in the treated rats was studied and Hematoxylin-Eosin (HE) staining or Oil red slices of liver and adipose tissue in the rats were examined as well. FDC shows excellent antioxidant and anti-glycation activity by attenuating lipid peroxidation. FDC determined in this investigation can become a potential solution to reduce obesity, to improve insulin sensitivity and be beneficial for the treatment of fat and diabetic patients. It is the first time to use the math model to determine the best ratio of three anti-oxidants, which can save much more time and chemical materials than traditional experimental method. This quantitative method represents a potentially new and useful strategy to screen all possible combinations of many natural anti-oxidants, therefore may help develop novel therapeutics with the potential to ameliorate the worldwide metabolic abnormalities., (Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.)

Poor absorption and bioavailability of procyanidins from the upper gastrointestinal tract result in the majority of the dose reaching the colon. During colonic transit, progressive microbial metabolism likely produces gradients of procyanidins and microbial metabolites along the length of the colon, suggesting that proximal and distal regions are exposed to different profiles of procyanidins and metabolites. However, previous studies have largely treated the colon as a single organ or looked at fecal profiles, and differences in the profiles of native and metabolite compounds between regions have not been observed. The metabolism kinetics of procyanidins larger than trimers and formation of metabolites in the colon have not been well characterized. Therefore, the objective of this study was to determine the kinetics of delivery and microbial metabolism of monomeric, dimeric and oligomeric procyanidins in the cecum and proximal, mid and distal colon. Sprague-Dawley rats were gavaged grape seed extract and sacrificed over 18 h. Analysis of luminal contents showed distinct native and metabolite profiles for each region. Procyanidins had maximum concentrations at approximately 3h postgavage for all sections. Metabolites reached maximum concentrations from 3 to 18 h postgavage. The appearance of metabolites was highly dependent on species: larger metabolites were found at earlier times in the more proximal segments, and smaller metabolites were found at later times in more distal regions. This study allowed for the observation of regions in the lower gastrointestinal tract, giving insight into the distribution and delivery of procyanidins and their microbial metabolites throughout the colon., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Proanthocyanidins (PAC) are a highly consumed class of flavonoids and their consumption has been linked to beneficial effects in type 2 diabetes. However, limited gastrointestinal absorption occurs due to the polymeric structure of PAC. We hypothesized that hydrolysis of the PAC polymer would increase bioavailability, thus leading to enhanced beneficial effects on glucose homeostasis and pancreatic β-cell function. PAC-rich pea seed coats (PSC) were supplemented to a high-fat diet (HFD) either in native (PAC) or hydrolyzed (HPAC) form fed to rats for 4 weeks. HFD or low-fat diet groups were controls. PAC-derived compounds were characterized in both PSC and serum. Glucose and insulin tolerance tests were conducted. Pancreatic α-cell and β-cell areas and glucose-stimulated insulin secretion (GSIS) from isolated islets were measured. Increased PAC-derived metabolites were detected in the serum of HPAC-fed rats compared to PAC-fed rats, suggesting hydrolysis of PSC-enhanced PAC bioavailability. This was associated with ~18% less (P<.05) weight gain compared to HFD without affecting food intake, as well as improvement in glucose disposal in vivo. There was a 2-fold decrease of α/β-cell area ratio and a 2.5-fold increase in GSIS from isolated islets of HPAC-fed rats. These results demonstrate that hydrolysis of PSC-derived PAC increased the bioavailability of PAC-derived products, which is critical for enhancing beneficial effects on glucose homeostasis and pancreatic β-cell function., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Urinary tract infections (UTI) are one of the most frequent extraintestinal infections caused by Escherichia coli (ExPEC). Cranberry juice has been used for decades to alleviate symptoms and prevent recurrent UTI. The putative compounds in cranberries are proanthocyanidins (PAC), specifically PAC with "A-type" bonds. Since PAC are not absorbed, their health benefits in UTI may occur through interactions at the mucosal surface in the gastrointestinal tract. Recent research showed that higher agglutination of ExPEC and reduced bacterial invasion are correlated with higher number of "A-type" bonds and higher degree of polymerization of PAC. An understanding of PAC structure-activity relationship is becoming feasible due to advancements, not only in obtaining purified PAC fractions that allow accurate estimation, but also in high-resolution MS methodologies, specifically, MALDI-TOF MS. A recent MALDI-TOF MS deconvolution method allows quantification of the ratios of "A-type" to "B-type" bonds enabling characteristic fingerprints. Moreover, the generation of fluorescently labeled PAC allows visualization of the interaction between ExPEC and PAC with microscopy. These tools can be used to establish structure-activity relationships between PAC and UTI and give insight on the mechanism of action of these compounds in the gut without being absorbed., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Proanthocyanidins are among the most abundant constituents in pine bark extracts (PBEs). This review summarizes medical research on PBEs from Pinus pinaster, Pinus radiata, Pinus massoniana, and other less well characterized species. The precise mechanisms of the important physiologic functions of PBE components remain to be elucidated, but there is evidently great potential for the identification and development of novel antioxidant, anti-inflammatory, cardiovascular, neuroprotective, and anticancer medicines. Although toxicological data for PBEs are limited, no serious adverse effects have been reported. PBEs, therefore, may have potential as nutraceuticals and pharmaceuticals and should be safe for use as food ingredients., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Obesity is a multifactorial disorder involving an abnormal or excessive amount of body fat. Obese people have a very high probability of developing metabolic syndrome, a condition in which cholesterol, lipid, and glucose levels rise, causing diabetes and heart disease. From the point of view of energy balance, the main contributors to obesity are excessive energy intake, inadequate energy expenditure and metabolic malfunctions. For this reason, health organisations are working to implement policies and plans to promote healthy eating and active living. However, these measures have not yet proven sufficient to combat this worldwide epidemic; therefore, drugs and bioactive compounds are being investigated to complement the existing strategies. In the present review, we discuss the available data regarding the modulation of obesity by proanthocyanidin rich extracts. Because studies with human subjects are very scarce, we focus on studies using laboratory animals. The results of in vitro studies are included because, although they cannot be directly extrapolated to the biological effects of proanthocyanidin, they can reveal some mechanisms of action.

Scope: Flavan-3-ols are abundant polyphenols in human nutrition and are associated with beneficial health effects. The aim of this study was to comparatively investigate the metabolic fate of (-)-epicatechin, procyanidin B1, and polymeric procyanidins in a randomized cross-over study in humans., Methods and Results: Parent compounds, conjugates, and microbial metabolites were determined in plasma, urine, and faeces by HPLC-MS and GC-MS/MS. Glucuronidated, sulfated, and methylated (-)-epicatechin and 5-(3',4'-dihydroxyphenyl)-valerolactone were the dominant metabolites in blood and urine. In addition, minor amounts of procyanidin B1 and 4-hydroxy-5-(3',4'-dihydroxyphenyl)valeric acid and their conjugated metabolites were detected. The formation of 5-(3',4'-dihydroxyphenyl)-valerolactone and 4-hydroxy-5-(3',4'-dihydroxyphenyl)valeric acid varied largely between individuals as well as with the degree of polymerization of flavan-3-ols. Monomer units were not detectable in plasma or urine after procyanidin B1 and polymeric procyanidin intake. No correlation was found between the intake of flavan-3-ols and the occurrence of phenolic acids in blood and urine or the phenolic compound profiles in faeces., Conclusion: In addition to conjugated metabolites derived from the absorption of monomeric flavan-3-ols, 5-(3',4'-dihydroxyphenyl)-valerolactone represents an important in vivo metabolite of (-)-epicatechin and procyanidin B1 produced by the gut microbiota., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Peanut skin is a rich source of polyphenols, such as proanthocyanidins. Peanut skin proanthocyanidins mainly consist of a subgroup called procyanidins. Peanut-based procyanidins contain oligomers of both type A and type B procyanidins. Recent studies have shown that peanut skin extracts exert protection against hepatic steatosis induced on rats fed with a high-fat diet. Studies have shown that proanthocyanidins protect against cardiovascular diseases (CVDs). The mechanism of CVD protection and hypolipidemic effect of peanut skin procyanidins has been gradually revealed in recent years. Due to the high molecular weight of procyanidins, they are not readily absorbed through the gut barrier. It is hypothesized that procyanidins exert their effect by inhibiting the absorption of dietary lipid and chylomicron secretion by enterocytes. In this review, we aim to highlight the hypolipidemic effects of peanut skin polyphenols and discuss the various molecular mechanisms, with which the polyphenols may exert the lipid-lowering function observed by weighing the absorption characteristics as well as gene expression mechanism responsible for lipid homeostasis.

Scope: Procyanidins (PCs) are among the most abundant polyphenols in the human diet and they are reported to exhibit several beneficial health effects. However, the knowledge about their metabolic fate is rather limited. To investigate the systemic absorption and metabolism of dietary PC B4, a kinetic study using pigs as model system has been performed., Methods and Results: After oral application of a single dose of 10 mg/kg body weight PC B4, urine and plasma were collected over a period of 48 h. PC B4 and its possible metabolites were analyzed in physiological samples using HPLC-MS/MS and GC-MS. PC B4 was detected as intact molecule in urine as well as in plasma. Maximum reached plasma concentration of PC B4 (cmax ) was 2.13 ng/mL (3.68 nM) and mean total urinary excretion related to the administered dose was 0.008 ± 0.003%. In addition to that the monomeric structural units catechin and epicatechin were determined as degradation products. Furthermore, methylated and conjugated monomeric metabolites were identified. Monomeric metabolites were identified to be the major fraction occurring in the systemic circulation. The analysis of phenolic acids did not show an increase of these possible further metabolites., Conclusion: After oral administration, PC B4 is absorbed as intact molecule and it is excreted in urine. In addition, it is degraded to the monomeric subunits that are then further metabolized to methylated and glucuronidated conjugates in pigs., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This study describes the development and validation of a liquid chromatography-mass spectrometry method for determination of a large number of flavanol colonic derivatives in biological samples. The method was validated with rat plasma after the intake of grape seed flavanols. The minimum plasma volume necessary to maintain good recovery values within the range of 83-110% for all of the standards was determined by micro solid-phase extraction (μ-SPE). In total, 16 commercial standards were used to measure 30 different phenolic compounds present at low concentration levels (micromolar). The chromatographic method enabled reliable quantification of plasma colonic flavanol derivatives with low limits of detection and quantification, achieving values of 0.03 nM and 0.10 nM, respectively. The developed method can be readily applied to determine all of the flavanol metabolites that are most likely responsible for the majority of biological effects of poorly absorbed flavanols.

Procyanidins have been extensively investigated for their potential health protective activities. However, the potential bioactivities of procyanidins are limited by their poor bioavailability. The majority of the ingested dose remains unabsorbed and reaches the colon where extensive microbial metabolism occurs. Most existing analytical methods measure either native compounds (catechins and procyanidins), or their microbial metabolites. The objectives of this study were to develop a high-throughput extraction and UPLC-MS/MS method for simultaneous measurement of both native procyanidins and their metabolites, facilitating high-throughput analysis of native and metabolite profiles in various regions of the colon. The present UPLC-MS/MS method facilitates simultaneous resolution and detection of authentic standards of 14 native catechin monomers and procyanidins, as well as 24 microbial metabolites. Detection and resolution of an additional 3 procyanidin dimers and 10 metabolites for which standards were not available was achieved. Elution and adequate resolution of both native compounds and metabolites were achieved within 10min. The intraday repeatability for native compounds was between 1.1 and 16.5%, and the interday repeatability for native compounds was between 2.2 and 25%. Intraday and interday repeatability for metabolites was between 0.6 and 24.1% and 1 and 23.9%, respectively. Observed lower limits of quantification for native compounds were ∼9-350fmol on-column, and for the microbial metabolites were ∼0.8-12,000fmol on-column. Observed lower limits of detection for native compounds were ∼4.5-190fmol on-column, and for metabolites were 0.304-6020fmol on-column. For native monomers and procyanidins, extraction recoveries ranged from 38 to 102%. Extraction recoveries for the 9 microbial metabolites tested ranged from 41 to 95%. Data from tissue analysis of rats gavaged with grape seed extract indicate fairly high accumulation of native compounds, primarily monomers and dimers, in the cecum and colon. Metabolite data indicate the progressive nature of microbial metabolism as the digesta moves through the lower GI tract. This method facilitates the high-throughput, sensitive, and simultaneous analysis of both native compounds and their microbial metabolites in biological samples and provides a more efficient means of extraction and analysis than previous methods., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Despite cranberry being associated with the prevention of bacterial infections for over a century, our understanding of the bioavailability and mechanisms by which cranberry prevents infection is limited. This study investigates the interactions between cranberry proanthocyanidins (CPAC) and human serum proteins (albumin, α-1-acid glycoprotein, and fibrinogen) that may be encountered during CPAC metabolism following ingestion. To better understand how CPAC might interfere with bacterial infection, we also examined the interactions between CPAC and selected bacterial virulence factors; namely, lipopolysaccharide (LPS) and rhamnolipid. The binding of CPAC to the serum proteins, rhamnolipids and LPS from Escherichia coli O111:B4 can be described by Langmuir-type isotherms, allowing the determination of the apparent adsorption affinity constants, with CPAC interacting most strongly with fibrinogen with a binding constant of 2.2 × 10(8) M(-1). These binding interactions will limit the bioavailability of the CPAC at the site of action, an important consideration in designing further clinical trials. Furthermore, CPAC interacts with Pseudomonas aeruginosa 10 LPS, E. coli O111:B4 LPS, and P. aeruginosa rhamnolipids in fundamentally different manners, supporting the theory that cranberry prevents bacterial infections via multiple mechanisms.

Peanut skin is a rich source of polyphenols including procyanidins and is shown to have hypolipidemic properties. This study investigated the bioavailability of peanut skin polyphenols using a rat model. First, the bioavailability of peanut skin polyphenols in rat plasma was evaluated. Our results showed procyanidin A2 levels in plasma peaked within 30 min of ingestion. The results of a second study show that peanut skin extract supplemented in addition to oil gavage resulted in significant decrease in plasma triglyceride and VLDL within 5h. In the third study, rats were given a Western type diet for 5 weeks with peanut skin extract at a dose of 150 and 300 mg/kg body weight. The main effects observed were lowering of total blood lipid and reduction of the plasma fatty acids profile. Our results suggest that procyanidin A may impart a key role of hypolipidemic effect seen in peanut skin polyphenols., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Apoptosis is a biological process necessary for maintaining cellular homeostasis. Several diseases can result if it is deregulated. For example, inhibition of apoptotic signaling pathways is linked to the survival of pathological cells, which contributes to cancer, whereas excessive apoptosis is linked to neurodegenerative diseases, partially via oxidative stress. The activation or restoration of apoptosis via extrinsic or intrinsic pathways combined with cell signaling pathways triggered by reactive oxygen specises (ROS) formation is considered a key strategy by which bioactive foods can exert their health effects. Proanthocyanidins, a class of flavonoids naturally found in fruits, vegetables, and beverages, have attracted a great deal of attention not only because they are strong antioxidants but also because they appear to exert a different modulation of apoptosis, stimulating apoptosis in damaged cells, thus preventing cancer or reducing apoptosis in healthy cells, and as a result, preserving the integrity of normal cells and protecting against neurodegenerative diseases. Therefore, proanthocyanidins could provide a defense against apoptosis induced by oxidative stress or directly inhibit apoptosis, and they could also provide a promising treatment for a variety of diseases. Emerging data suggest that proanthocyanidins, especially those that humans can be persuaded to consume, may be used to prevent and manage cancer and mental disorders.

Epidemiologic studies indicate that millions of people suffer from recurrent cystitis, a pathology requiring antibiotic prophylaxis and entailing high social costs. Cranberry is a traditional folk remedy for cystitis and, which, in the form of a variety of products and formulations has over several decades undergone extensive evaluation for the management of urinary tract infections (UTI). The aim of this retrospective study is to summarize and review the most relevant and recent preclinical and clinical studies on cranberries for the treatment of UTIs. The scientific literature selected for this review was identified by searches of Medline via PubMed. A variety of recent experimental evidence has shed light on the mechanism underlying the anti-adhesive properties of proanthrocyanidins, their structure-activity relationships, and pharmacokinetics. Analysis of clinical studies and evaluation of the cranberry efficacy/safety ratio in the prevention of UTIs strongly support the use of cranberry in the prophylaxis of recurrent UTIs in young and middle-aged women. However, evidence of its clinical use among other patients remains controversial.

The regular consumption of flavonoids has been associated with reduced mortality and a decreased risk of cardiovascular diseases. The proanthocyanidins found in plasma are very different from the original flavonoids in food sources. The use of physiologically appropriate conjugates of proanthocyanidins is essential for the in vitro analysis of flavonoid bioactivity. In this study, the effect of different proanthocyanidin-rich extracts, which were obtained from cocoa (CCX), French maritime pine bark (Pycnogenol extract, PYC) and grape seed (GSPE), on lipid homeostasis was evaluated. Hepatic human cells (HepG2 cells) were treated with 25 mg/L of CCX, PYC or GSPE. We also performed in vitro experiments to assess the effect on lipid synthesis that is induced by the bioactive GSPE proanthocyanidins using the physiological metabolites that are present in the serum of GSPE-administered rats. For this, Wistar rats were administered 1 g/kg of GSPE, and serum was collected after 2 h. The semipurified serum of GSPE-administered rats was fully characterized by liquid chromatography tandem triple quadrupole mass spectrometry (LC-QqQ/MS(2)). The lipids studied in the analyses were free cholesterol (FC), cholesterol ester (CE) and triglycerides (TG). All three proanthocyanidin-rich extracts induced a remarkable decrease in the de novo lipid synthesis in HepG2 cells. Moreover, GSPE rat serum metabolites reduced the total percentage of CE, FC and particularly TG; this reduction was significantly higher than that observed in the cells directly treated with GSPE. In conclusion, the bioactivity of the physiological metabolites that are present in the serum of rats after their ingestion of a proanthocyanidin-rich extract was demonstrated in Hep G2 cells., (© 2013.)

Scope: Polyphenols have been demonstrated to provide health benefits affecting cellular and physiological processes. This study aims to evaluate the bioavailability and distribution of grape seed flavanol compounds during pregnancy and whether fetuses could be exposed to these compounds., Methods and Results: The distribution of flavanols and their metabolites in rat plasma, liver, white adipose tissue, brain, amniotic fluid, placenta, and fetuses after 1 and 2 h of an acute intake of a grape seed proanthocyanidin extract was examined by LC-ESI-TOF/MS. Flavanols and their metabolites were widely distributed in both pregnant and nonpregnant rat plasma and tissues. In liver, the conjugated forms of flavanols were less available in pregnant than nonpregnant rats. Flavanol metabolites were abundant in maternal placenta but detected at low levels in fetuses and amniotic fluid., Conclusion: Flavanol metabolization appears to be less active in the liver during pregnancy. Moreover, data indicated that transport across the placenta is not efficient and for flavanols and their metabolites, the placenta seems to act as a barrier. However, these compounds target the fetus and are excreted in the amniotic fluid., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Current evidence shows that monomeric flavonoids are known to be only slightly absorbed in the small intestine, but the metabolism of oligomeric and polymeric proanthocyanidins (PAC) in the colon is poorly understood. The objective of this study was to optimize the analysis of grape seed extract (GSE) in feces and use that method to assess the presence of PAC in the colon after ingestion of GSE. Rats were fed a diet ad libitum containing 0.25% (w/w) GSE for 10 days. Feces were collected daily and colonic contents at sacrifice on day 10, respectively. The recovery of fecal PAC using a solid-phase extraction (SPE) method was >70%. PAC were separated by normal-phase HPLC with fluorescence detection, and subsequent peak confirmation was done by MS-ion trap. The concentration of colonic contents at day 10 was 13.9 mg/kg for monomer, and those for oligomers (dimers-hexamers) were 33.4, 84.6, 87.2, 57.3, and 35.7 mg/kg, respectively. The concentration of monomeric and oligomeric PAC in daily feces was similar among days. In the mass balance analysis, approximately 11% of ingested PAC was recovered in the feces. These findings indicate that ingested PAC were present in the colon as the intact parent compounds and thus may contribute to the health of the gastrointestinal tract.

The inflammatory response has been implicated in the pathogenesis of many chronic diseases. Thus, the modulation of the inflammatory response by the consumption of bioactive food compounds, such as procyanidins, is a powerful tool to promote health. Procyanidin-mediated anti-inflammatory molecular mechanisms include, among others, the modulation of the arachidonic acid pathway, the inhibition of the gene transcription, protein expression and enzymatic activity of eicosanoid generating enzymes, the production and secretion of inflammatory mediators (such as cytokines and nitric oxide), the inhibition of mitogen-activated protein kinase (MAPK) pathway activation, and the modulation of the nuclear factor-κB (NF-κB) pathway. The NF-κB pathway can be regulated by procyanidins at several levels. During early events in NF-κB signaling, procyanidins modulate Iκκ activity, and the cytoplasmic retention of p65:p50 NF-κB by the inhibition of IκB phosphorylation and proteasomal degradation, while at late stages, they affect the nuclear translocation of pro/anti-inflammatory NF-κB homo/hetero dimers and their subsequent binding to the promoter regions of target genes. To identify and understand the value of procyanidins in the modulation of the inflammatory response, the molecular mechanisms underlying the anti-inflammatory activities and prohomeostatic effects of procyanidins need to be investigated further., (Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.)

While polyphenolic compounds have many health benefits, the potential development of polyphenols for the prevention/treatment of neurological disorders is largely hindered by their complexity as well as by limited knowledge regarding their bioavailability, metabolism, and bioactivity, especially in the brain. We recently demonstrated that dietary supplementation with a specific grape-derived polyphenolic preparation (GP) significantly improves cognitive function in a mouse model of Alzheimer's disease (AD). GP is comprised of the proanthocyanidin (PAC) catechin and epicatechin in monomeric (Mo), oligomeric, and polymeric forms. In this study, we report that following oral administration of the independent GP forms, only Mo is able to improve cognitive function and only Mo metabolites can selectively reach and accumulate in the brain at a concentration of ∼400 nM. Most importantly, we report for the first time that a biosynthetic epicatechin metabolite, 3'-O-methyl-epicatechin-5-O-β-glucuronide (3'-O-Me-EC-Gluc), one of the PAC metabolites identified in the brain following Mo treatment, promotes basal synaptic transmission and long-term potentiation at physiologically relevant concentrations in hippocampus slices through mechanisms associated with cAMP response element binding protein (CREB) signaling. Our studies suggest that select brain-targeted PAC metabolites benefit cognition by improving synaptic plasticity in the brain, and provide impetus to develop 3'-O-Me-EC-Gluc and other brain-targeted PAC metabolites to promote learning and memory in AD and other forms of dementia.

Scope: Aim of this study was to investigate urinary excretion and metabolism of procyanidins a group of secondary plant metabolites with many beneficial health effects described in literature., Methods and Results: To investigate the metabolism of procyanidins in the absence of flavan-3-ols, centrifugal partition chromatography was used for their reduction in a grape seed extract to a level of almost zero. After administration of the monomer reduced grape seed extract (mredGSE) containing procyanidins B1, B2, B3, B4, C1 to pigs flavan-3-ols, their methyl derivatives, dimeric and trimeric procyanidins were determined in urine by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Maximal concentrations of procyanidins 6 h after administration vary from 5 to 30 ng/mg creatinine. Total excretion of flavan-3-ols and their methyl derivatives indicates an increasing trend for pigs given mredGSE in comparison to pigs of the control group. Flavan-3-ols were conjugated and methylated to a great extent in comparison to dimeric and trimeric procyanidins. In the case of low molecular weight metabolites, an increasing trend was observed for hippuric acid, not for phenolic acids., Conclusions: Ratios of total excretion of procyanidins to administrated amounts between 0.004% (C1) and 0.019% (B4) suggest a poor urinary excretion by pigs. A transfer of these results to humans is possible due to their similar gastrointestinal tract., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)