Bioavailability Of Phenolic Acids Research Articles

An Insight into the Functional Benefit of Phenolic Acids from Whole Grains: An Update

Abstract: Plant metabolites are known for their beneficial effects on human health. Whole grains are also called as a virtuous source of staple food and phenolic acids. These acids are present in whole grains abundantly in three forms, free, conjugated, and bound. From the entire content of phenolic acids in whole grains, an abundance of bound phenolic acids is about 70-95%. The bioavailability of phenolic acids varies from simple molecules to complex molecules. However, mechanical cooking influences phenolic acid's structural and functional composition. These natural phenolic acids exhibit several pharmacological activities such as antioxidant effect, antiinflammatory, antimicrobial, and anticancer properties within the physiological system. The present review covers the research and development of crucial whole grain products and nutraceuticals by providing insights to analytical methods, bioavailability, bioaccessibility and health benefits of phenolic acids. Additionally, this review encompasses recent information on the evaluation of complete grains, including contemporary strategies for assessing the bioavailability of phenolic acid.

Oral Pharmacokinetics of Hydroxycinnamic Acids: An Updated Review.

Hydroxycinnamic acids (HCAs) such as caffeic acid (CA), chlorogenic acid (CGA), coumaric acid (COA) isomers, ferulic acid (FA) and rosmarinic acid (RA) are natural phenolic acids with widespread distribution in vegetal foods and well-documented pharmacological activities. However, the low bioavailability of HCAs impairs their administration by the oral route. The present review addresses new findings and important factors/obstacles for their oral administration, which were unexplored in the reviews published a decade ago concerning the bioavailability of phenolic acids. Based on this, the article aims to perform an updated review of the water solubility and gastrointestinal stability of HCAs, as well as describe their oral absorption, distribution, metabolism and excretion (ADME) processes by in vitro, ex vivo, in situ and in vivo methods.

Ketone Analog of Caffeic Acid Phenethyl Ester Exhibits Antioxidant Activity via Activation of ERK-Dependent Nrf2 Pathway

Due to their robust antioxidant properties, phenolic acids and their analogs are extensively studied for their ability to activate cellular antioxidant pathways, including nuclear factor (erythroid-derived-2)-like 2 (Nrf2)-antioxidant response element (ARE) pathway. Caffeic, ferulic, and gallic acid are well-studied members of phenolic acids. Constant efforts are made to improve the pharmacological effects and bioavailability of phenolic acids by synthesizing their chemical derivatives. This study determines how modifications of the chemical structure of these phenolic acids affect their antioxidant and cytoprotective activities. We have selected six superior antioxidant compounds (12, 16, 26, 35, 42, and 44) of the 48 caffeic acid phenethyl ester (CAPE) analogs based on their ability to scavenge free radicals in vitro using standard antioxidant assays. These compounds exhibited minimal toxicity as indicated by cell cycle and cytochrome C release assays. Among these compounds, 44, the ketone analog of CAPE, exhibited the ability to increase p-Nrf2 (Ser40) levels in 293T cells (p < 0.05). Further, 44, exhibited its antioxidant effect in Drosophila Melanogaster as indicated by an increase in mRNA levels of Nrf2 and GPx (p < 0.05). Finally, the ability of 44 to activate the antioxidant pathway was abolished in the presence of extracellular signal-regulated kinase (ERK) inhibitor in 293T cells. Thus, we identify 44, the ketone analog of CAPE, as a unique antioxidant molecule with the function of ERK-mediated Nrf2 activation.

Administration Time Significantly Affects Plasma Bioavailability of Grape Seed Proanthocyanidins Extract in Healthy and Obese Fischer 344 Rats.

Phenolic compounds are bioactive molecules that are associated with several health benefits. Metabolization and absorption are the main determinants of their bioavailability and bioactivity. Thus, the study of the factors that modulate these processes, such as sex or diet is essential. Recently, it has been shown that biological rhythms may also play a key role. Hence, the aim of this study is to evaluate if the bioavailability of a grape proanthocyanidin extract (GSPE) is affected by the administration time in an animal model of metabolic syndrome (MetS). Female and male Fischer 344 rats are fed either a standard or a cafeteria diet (CAF) for 9 weeks, and an oral dose of GSPE (25mg kg-1 ) is daily administered either at 8:00 am (zeitgeber time (ZT)-0) or at 8:00 pm (ZT-12) during the last 4 weeks. Plasma phenolic compounds are then quantified by liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). Phase-II and gut microbiota-derived phenolic metabolites are affected by ZT in all conditions or only in obese rats, respectively. CAF feeding affected the bioavailability of phenolic acids and free flavan-3-ols. Differences due to sex are also observed. These findings demonstrate that ZT, diet, and sex are key factors influencing phenolic compounds bioavailability.

Electrophoretic Light Scattering and Electrochemical Impedance Spectroscopy Studies of Lipid Bilayers Modified by Cinnamic Acid and Its Hydroxyl Derivatives.

Pharmacological efficiency of active compounds is largely determined by their membrane permeability. Thus, identification of drug-membrane interactions seems to be a crucial element determining drug-like properties of chemical agents. Yet, knowledge of this issue is still lacking. Since chemoprevention based on natural compounds such as cinnamic acid (CinA), p-coumaric acid (p-CoA) and ferulic (FA) is becoming a strong trend in modern oncopharmacology, determination of physicochemical properties of these anticancer compounds is highly important. Here, electrophoretic light scattering and impedance spectroscopy were applied to study the effects of these phenolic acids on electrical properties of bilayers formed from 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-diacyl-sn-glycero-3-phospho-l-serine (PS) or DOPC-PS mixture. After phenolic acid treatment, the negative charge of membranes increased in alkaline pH solutions, but not in acidic ones. The impedance data showed elevated values of both the electrical capacitance and the electrical resistance. We concluded that at acidic pH all tested compounds were able to solubilize into the membrane and permeate it. At neutral and alkaline pH, the CinA could be partially inserted into the bilayers, whereas p-CoA and FA could be anchored at the bilayer surface. Our results indicate that the electrochemical methods might be crucial for predicting pharmacological activity and bioavailability of phenolic acids.

Increased bioavailability of phenolic acids and enhanced vascular function following intake of feruloyl esterase-processed high fibre bread: A randomized, controlled, single blind, crossover human intervention trial

Clinical trial data have indicated an association between wholegrain consumption and a reduction in surrogate markers of cardiovascular disease. Phenolics present in wholegrain bound to arabinoxylan fibre may contribute these effects, particularly when released enzymatically from the fiber prior to ingestion. The aim of the present study was therefore to determine whether the intake of high fibre bread containing higher free ferulic acid (FA) levels (enzymatically released during processing) enhances human endothelium-dependent vascular function. A randomized, single masked, controlled, crossover, human intervention study was conducted on 19 healthy men. Individuals consumed either a high fibre flatbread with enzymatically released free FA (14.22mg), an equivalent standard high fibre bread (2.34mg), or a white bread control (0.48mg) and markers of vascular function and plasma phenolic acid concentrations were measured at baseline, 2, 5 and 7h post consumption. Significantly increased brachial arterial dilation was observed following consumption of the high free FA ('enzyme-treated') high fibre bread verses both a white bread (2h: p<0.05; 5h: p<0.01) and a standard high fibre bread (5h: p<0.05). Concurrently, significant increases in plasma FA levels were observed, at 2h (p<0.01) after consumption of the enzyme-treated bread, relative to control treatments. Blood pressure, heart rate, DVP-SI and DVP-RI were not significantly altered following intake of any of the breads (p>0.05). Dietary intake of bread, processed enzymatically to release FA from arabinoxylan fiber during production increases the bioavailability of FA, and induces acute endothelium-dependent vasodilation. NO: NCT03946293. WEBSITE: www.clinicaltrials.gov.

In vitro Antioxidant, Anti-inflammatory, Anti-metabolic Syndrome, Antimicrobial, and Anticancer Effect of Phenolic Acids Isolated from Fresh Lovage Leaves [Levisticum officinale Koch] Elicited with Jasmonic Acid and Yeast Extract.

Lovage seedlings were elicited with jasmonic acid (JA) and yeast extract (YE) to induce the synthesis of biologically active compounds. A simulated digestion process was carried out to determine the potential bioavailability of phenolic acids. Buffer extracts were prepared for comparison. The ability to neutralize ABTS radicals was higher in all samples after the in vitro digestion, compared to that in the buffer extracts. However, the elicitation resulted in a significant increase only in the value of the reduction power of the potentially bioavailable fraction of phenolic acids. The effect of the elicitation on the activity of the potentially bioavailable fraction of phenolic acids towards the enzymes involved in the pathogenesis of the metabolic syndrome, i.e., ACE, lipase, amylase, and glucosidase, was analyzed as well. The in vitro digestion caused a significant increase in the ability to inhibit the activity of these enzymes; moreover, the inhibitory activity against alpha-amylase was revealed only after the digestion process. The potential anti-inflammatory effect of the analyzed extracts was defined as the ability to inhibit key pro-inflammatory enzymes, i.e., lipoxygenase and cyclooxygenase 2. The buffer extracts from the YE-elicited lovage inhibited the LOX and COX-2 activity more effectively than the extracts from the control plants. A significant increase in the anti-inflammatory and antimicrobial properties was noted after the simulated digestion.

The Gut Microbiota Composition Affects Polyphenol-mediated Cognitive Resilience in Mice by Modulating the Bioavailability of Phenolic Acids (P20-038-19)

ObjectivesDietary polyphenols promote memory in models of sleep deprivation (SD), stress, and neurodegeneration. The biological properties of dietary polyphenols greatly depend on the bioavailability of their phenolic metabolites derivatives that are modulated by gut microbiota. We recently demonstrated that supplementation with grape-derived bioactive dietary polyphenol preparation (BDPP) improves SD-induced cognitive impairment. MethodsThis study examined the role of gut microbiota in BDPP’s memory promotion effect in SD. C57BL6/J mice, treated with antibiotics or BDPP or both were sleep-deprived at the end of a fear conditioning training session and fear memory was assessed the next day. Gut microbiota composition was analyzed in fecal samples and BDPP-driven phenolic acid metabolites extraction was measured in plasma. ResultsWe report that the beneficial effect of BDPP on memory in SD is attenuated by antibiotics-induced dysbiosis. We identified specific communities of fecal microbiota that associate with the bioavailability of BDPP-derived phenolic acids, which in turn, associated with memory promotion. ConclusionsThese results suggest the gut microbiota composition significantly affects the bioavailability of phenolic acids that drive the dietary polyphenols’ cognitive resilience property. Our findings provide a preclinical model to test causal association of gut microbiota-polyphenols in the potential development of dietary polyphenols for the prevention/treatment of cognitive impairment. Funding SourcesThis project was funded a P50 CARBON Center grant from NCCIH/ODS (Pasinetti, PD/PI).

The gut microbiota composition affects dietary polyphenols-mediated cognitive resilience in mice by modulating the bioavailability of phenolic acids

Dietary polyphenols promote memory in models of sleep deprivation (SD), stress, and neurodegeneration. The biological properties of dietary polyphenols greatly depend upon the bioavailability of their phenolic metabolites derivatives, which are modulated by gut microbiota. We recently demonstrated that supplementation with grape-derived bioactive dietary polyphenol preparation (BDPP) improves SD-induced cognitive impairment. This study examined the role of the gut microbiota in the ability of BDPP to prevent memory impairment in response to SD. C57BL6/J mice, treated with antibiotics mix (ABX) or BDPP or both, were sleep-deprived at the end of a fear conditioning training session and fear memory was assessed the next day. Gut microbiota composition was analyzed in fecal samples and BDPP-driven phenolic acid metabolites extraction was measured in plasma. We report that the beneficial effect of BDPP on memory in SD is attenuated by ABX-induced dysbiosis. We identified specific communities of fecal microbiota that are associated with the bioavailability of BDPP-derived phenolic acids, which in turn, are associated with memory promotion. These results suggest the gut microbiota composition significantly affects the bioavailability of phenolic acids that drive the dietary polyphenols’ cognitive resilience property. Our findings provide a preclinical model with which to test the causal association of gut microbiota-polyphenols, with the ultimate goal of potential developing dietary polyphenols for the prevention/treatment of cognitive impairment.

Changes in Phenolic Acid Content in Maize during Food Product Processing.

The notion that many nutrients and beneficial phytochemicals in maize are lost due to food product processing is common, but this has not been studied in detail for the phenolic acids. Information regarding changes in phenolic acid content throughout processing is highly valuable because some phenolic acids are chemopreventive agents of aging-related diseases. It is unknown when and why these changes in phenolic acid content might occur during processing, whether some maize genotypes might be more resistant to processing induced changes in phenolic acid content than other genotypes, or if processing affects the bioavailability of phenolic acids in maize-based food products. For this study, a laboratory-scale processing protocol was developed and used to process whole maize kernels into toasted cornflakes. High-throughput microscale wet-lab analyses were applied to determine the concentrations of soluble and insoluble-bound phenolic acids in samples of grain, three intermediate processing stages, and toasted cornflakes obtained from 12 ex-PVP maize inbreds and seven hybrids. In the grain, insoluble-bound ferulic acid was the most common phenolic acid, followed by insoluble-bound p-coumaric acid and soluble cinnamic acid, a precursor to the phenolic acids. Notably, the ferulic acid content was approximately 1950 μg/g, more than ten-times the concentration of many fruits and vegetables. Processing reduced the content of the phenolic acids regardless of the genotype. Most changes occurred during dry milling due to the removal of the bran. The concentration of bioavailable soluble ferulic and p-coumaric acid increased negligibly due to thermal stresses. Therefore, the current dry milling based processing techniques used to manufacture many maize-based foods, including breakfast cereals, are not conducive for increasing the content of bioavailable phenolics in processed maize food products. This suggests that while maize is an excellent source of phenolics, alternative or complementary processing methods must be developed before this nutritional resource can be utilized.

Hydrolysis of Nonpolar n-Alkyl Ferulates by Feruloyl Esterases.

Ferulic acid is one of the major phenolic acids in plants and can be found esterified to plant cell wall components, but also as long-chain n-alkyl and steryl esters. Microbial feruloyl esterases may play a role in the bioavailability of phenolic acids during human and animal digestion. It is therefore of interest if feruloyl esterases are capable of hydrolyzing nonpolar ferulic acid esters. A series of n-alkyl ferulates with increasing lipophilicity were enzymatically synthesized, and the kinetic constants of their hydrolysis by four feruloyl esterases and a lipase as control were determined. A decrease in Km and kcat could be observed with decreased substrate polarity for all of the feruloyl esterases. Only one feruloyl esterase and the control lipase showed hydrolytic activity toward octadecyl ferulate. These results led to the conclusion that lipophilic ferulates are poor substrates for known feruloyl esterases and more specific esterases/lipases need to be identified.

Effect of chito-oligosaccharide on the oral absorptions of phenolic acids of Flos Lonicerae extract

Phenolic acids, the main active ingredients in Flos Lonicerae extract possess strong antibacterial, antioxidant and antiviral effects, and their contents was higher largely than that of other ingredients such as flavones, but the absolute bioavailability orally was significantly low, which is significant low influencing clinical efficacies of its oral preparations. In the present study, in vitro Caco-2 cell, in situ single-pass intestinal perfusion and in vivo pharmacokinetics study were performed to investigate the effects of COS on the intestinal absorption of phenolic acids. The pharmacological effects such as antiviral activity improvement by COS were verified by MDCK cell damage inhibition rate after influenza virus propagation. The observations from in vitro Caco-2 cell showed that the absorption of phenolic acids in Flos Lonicerae extract could be improved by COS. Meanwhile, COS at the same low, medium and high concentrations caused a significant, concentration-dependent increase in the Papp-value for phenolic acids compared to the control group (p<0.05), and was all safe for the Caco-2 cells. The observations from single-pass intestinal perfusion in situ model showed that the intestinal absorption of phenolic acids can be enhanced by COS. Meanwhile, the absorption enhancing effect of phenolic acids might be saturable in different intestine sites. In pharmacokinetics study, COS at dosage of 25mg/kg improved the bioavailability of phenolic acids in Flos Lonicerae extract to the greatest extent, and was safe for gastrointestine from morphological observation. Besides, treatment with Flos Lonicerae extract with COS at dosage of 25mg/kg prevented MDCK cell damage upon influenza virus propagation better than that of control. All findings above suggested that COS at dosage of 25mg/kg might be safe and effective absorption enhancer for improving the bioavailability of phenolic acids and the antiviral activity in vitro in Flos Lonicerae extract.

Bioprocessing of Wheat Bran in Whole Wheat Bread Increases the Bioavailability of Phenolic Acids in Men and Exerts Antiinflammatory Effects ex Vivo

Whole grain consumption has been linked to a lower risk of metabolic syndrome, which is normally associated with a low-grade chronic inflammation. The benefits of whole grain are in part related to the inclusion of the bran, rich in phenolic acids and fiber. However, the phenols are poorly bioaccessible from the cereal matrix. The aim of the present study was to investigate the effect of bioprocessing of the bran in whole wheat bread on the bioavailability of phenolic acids, the postprandial plasma antioxidant capacity, and ex vivo antiinflammatory properties. After consumption of a low phenolic acid diet for 3 d and overnight fasting, 8 healthy men consumed 300 g of whole wheat bread containing native bran (control bread) or bioprocessed bran (bioprocessed bread) in a cross-over design. Urine and blood samples were collected for 24 h to analyze the phenolic acids and metabolites. Trolox equivalent antioxidant capacity was measured in plasma. Cytokines were measured in blood after ex vivo stimulation with LPS. The bioavailabilities of ferulic acid, vanillic acid, sinapic acid, and 3,4-dimethoxybenzoic acid from the bioprocessed bread were 2- to 3-fold those from the control bread. Phenylpropionic acid and 3-hydroxyphenylpropionic acid were the main colonic metabolites of the nonbioaccessible phenols. The ratios of pro-:antiinflammatory cytokines were significantly lower in LPS-stimulated blood after the consumption of the bioprocessed bread. In conclusion, bioprocessing can remarkably increase the bioavailability of phenolic acids and their circulating metabolites, compounds which have immunomodulatory effects ex vivo.

Bioavailability of phenolic acids

Two large classes of phenolic acids were comprised in this review: benzoic acid derivatives and cinnamic acid derivatives. They have been found to be very extended in fruits and vegetables at different concentrations. For example, hydroxycinnamic acids concentration was higher than that found for hydroxybenzoic acids. Concerning their consumption, hydroxycinnamic acids provide larger contributions to the total polyphenol intake than benzoic acid derivatives or flavonoids. This phenolic acid intake is led by the coffee intake since it has very rich concentrations in hydroxycinnamic acids. Moreover, several experimental and epidemiological studies report the protection of phenolic acids against various degenerative diseases. However, despite all these interesting attributions and even if phenolic acids are the main polyphenols consumed, their bioavailability has not received as attention as that flavonoids. This concept is an essential step to understand the health-promoting properties of phenolic acids and to serve as tool to design in vivo and in vitro experiments to know their biological properties. Therefore, a compilation of bioavailability data of phenolic acids have been presented here paying attention to the two types of phenolic acid bioavailability, direct and indirect derived from the direct phenolic acid and flavonoid consumption, respectively. Then, a new relevant concept which may be named as total bioavailability of phenolic acids includes the direct absorption and metabolism of phenolic acids from food consumption and phenolic acids bioavailability as a result of the cleavage on the main skeleton ring of flavonoids by the gut microflora.

Prediction of bioavailability of phenolic acids by potentiometric titration method and chromatographic techniques

Early screening of physico-chemical and ADME (Absorption, Distribution, Metabolism and Elimination) properties has become the key interest in drug discovery. Molecular lipophilicity is a major physico-chemical property, which describes oral absorption, cell uptake, protein binding, blood-brain penetration and metabolism of the bioactive substances. Phenolic acids (a group of molecules present in majority of plants) exhibit protective effects against many diseases, but whether they can reach their sites of action, particularly in humans, is largely unknown. The aim of our work was to investigate several ADME parameters of 8 phenolic acids by chromatographic techniques (RP-TLC and RP-HPLC) and potentiometric titration method. Nowadays chromatography has a tendency to replace tedious ˝shake-flask˝ method for measuring lipophilicity. The TLC measurements were performed on 10x20 cm glass plates precoated with RP-18F254s. The HPLC measurements were performed using Agilent 1100 LC System, with ZORBAX SB-C18, 4.6x150 mm, 3.5 μ m particle size column. The binary solvent system, methanol– phosphate buffer (pH=2.5), was used as a mobile phase in both techniques with a varying content of organic modifier (80-5%). The potentiometric titration method was chosen to get detailed information on the partitioning characteristics of target compounds at all pH values. pKa values and lipophilic pH-profiles were determined using Sirius instrument GLpKa. Linear regression has shown good correlation between RM(TLC) and logkw(HPLC) values (r=0.96). The correlation between experimental data and ADME parameters predicted by different computer programs was considered in order to evaluate the predictive power of the theoretical approaches applied to predict the lipophilicity of phenolic acids. Moderate correlations (r<0.90) between experimental and theoretical values demand constant evaluation of calculated data validity.

Sorption?desorption of phenolic acids as affected by soil properties

Phenolic acids have been implicated in the process of allelopathy and are, therefore, of interest in plant management as a basis for new herbicide structures. The potential bioavailability of phenolic acids is controlled by sorption–desorption processes in soil. Sorption–desorption of p-coumaric acid (4-hydroxycinnamic acid), ferulic acid (3-methoxy-4-hydroxycinnamic acid), veratric acid (3,4-dimethoxybenzoic acid), vanillic acid (3-methoxy-4-hydroxybenzoic acid), and p-hydroxybenzoic acid (4-hydroxybenzoic acid) was characterized on soils with varying physicochemical properties. The phenolic acids sorbed quickly (<8 h) and in high proportions to the amount applied (average 84% of applied was sorbed). Sorption was irreversible with the batch desorption method used (0.01 N CaCl2 extraction). Pretreatment of soils to remove organic matter and free metal oxides from the soils decreased sorption, particularly in soils with free oxides removed. Statistical analysis suggested that sorption of p-coumaric and ferulic acids was correlated with soil clay content and veratric acid sorption was correlated with several soil factors. In contrast, no consistent relationship between soil characteristics and vanillic and p-hydroxybenzoic acid sorption was found. Based on the results of these experiments, i.e. the high reactivity of the phenolic acids, it is unlikely that these chemicals would be transported far from their point of origin, limiting their range of influence. It appears that, for phenolic acids to have allelopathic effects on plants, they would have to persist in the soil for long periods, resulting in a buildup of the chemical to high enough levels so that sufficient chemical would be in solution to cause the allelopathic effects, even though they may be strongly sorbed at lower concentrations.