Absorbed Bioactive Compounds Replicate Guanxin II-Induced Endothelium-Associated in/ex vivo Vasodilation.

OBJECTIVE: To develop an interference-free and rapid method to elucidate Guanxin II (GX II)'s representative vasodilator absorbed bioactive compounds (ABCs) among enormous phytochemicals. METHODS: The contents of ferulic acid, tanshinol, and hydroxysafflor yellow A (FTA) in GX II/rat serum after the oral administration of GX II (30 g/kg) were detected using ultra-performance liquid chromatography-mass spectrometry. Totally 18 rats were randomly assigned to the control group (0.9% normal saline), GX II (30 g/kg) and FTA (5, 28 and 77 mg/kg) by random number table method. Diastolic coronary flow velocity-time integral (VTI), i.e., coronary flow or coronary flow-mediated dilation (CFMD), and endothelium-intact vascular tension of isolated aortic rings were measured. After 12 h of exposure to blank medium or 0.5 mmol/L H2O2, endothelial cells (ECs) were treated with post-dose GX II of supernatant from deproteinized serum (PGSDS, 300 µL PGSDS per 1 mL of culture medium) or FTA (237, 1539, and 1510 mg/mL) for 10 min as control, H2O2, PGSDS and FTA groups. Nitric oxide (NO), vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), superoxide dismutase (SOD), malondialdehyde (MDA) and phosphorylated phosphoinositide 3 kinase (p-PI3K), phosphorylated protein kinase B (p-AKT), phosphorylated endothelial nitric oxide synthase (p-eNOS) were analyzed. PGSDS was developed as a GX II proxy of ex vivo herbal crude extracts. RESULTS: PGSDS effectively eliminates false responses caused by crude GX II preparations. When doses equaled the contents in GX II/its post-dose serum, FTA accounted for 98.17% of GX II -added CFMD and 92.99% of PGSDS-reduced vascular tension. In ECs, FTA/PGSDS was found to have significant antioxidant (lower MDA and higher SOD, P<0.01) and endothelial function-protective (lower VEGF, ET-1, P<0.01) effects. The increases in aortic relaxation, endothelial NO levels and phosphorylated PI3K/Akt/eNOS protein induced by FTA/PGSDS were markedly abolished by NG-nitro-L-arginine methyl ester (L-NA, eNOS inhibitor) and wortmannin (PI3K/AKT inhibitor), respectively, indicating an endothelium-dependent vasodilation via the PI3K/AKT-eNOS pathway (P<0.01). CONCLUSION: This study provides a strategy for rapidly and precisely elucidating GX II's representative in/ex vivo cardioprotective absorbed bioactive compounds (ABCs)-FTA, suggesting its potential in advancing precision ethnomedicine.

Ferulic acid-loaded nanocapsules: Evaluation of mucosal interaction, safety and antioxidant activity in human mononucleated cells.

Ferulic acid (FA) is a phenolic compound that has antioxidant, anti-inflammatory and anticarcinogenic properties besides presenting cytoprotective activity. It has limited oral bioavailability what is a challenge to its therapeutic application. In this way, this investigation aimed to develop FA-loaded nanocapsule suspensions (NC-FA) prepared with ethylcellulose and evaluate their in vitro release profile, mucoadhesion and irritation potential; scavenging capacity, cytotoxicity, cytoprotection and genoprotection against hydrogen peroxide-induced damage in hMNC (human Mononucleated Cells) culture. The nanocapsules presented physicochemical characteristics compatible with colloidal systems (NC-FA: 112 ± 3 nm; NC-B (without FA): 107 ± 3 nm; PdI < 0.2; Span<2.0 and negative zeta potential). In addition, the nanoparticulate system promoted the FA controlled release, increasing the half-life twice through the in vitro dialysis method. NC-FA and NC-B were able to interact with mucin, which is an indicative of mucoadhesive properties and the association of FA with nanocapsules showed decreased irritation by HET-CAM method. Besides, the NC-FA did not present cytotoxicity in hMNC and improved the ATBS radical scavenging capacity. Besides, it prevented, treated and reversed oxidative conditions in a H2O2-induced model in hMNC. Thus, this nanocarrier formulation is promising to perform more preclinical investigations focusing on diseases involving oxidative mechanisms.

Potential bioaccessibility of phenolic acids in whole wheat products during in vitro gastrointestinal digestion and probiotic fermentation.

Health benefits of whole wheat products are partially attributed by their unique phenolic compounds. This study investigated effect of simulated gastrointestinal digestion and probiotic fermentation on releasing of phenolic acids from whole wheat foods (bread, cookie, and pasta). Kinetics results showed that more phenolic acids were released within the first hour of gastric and intestinal digestions compared to the prolonged digestion. Lactobacillus rhamnosus GG, a common probiotic strain, released additional phenolic acids from the digestive residues during fermentation. Simulated digestion released more soluble trans-ferulic acid than chemical extraction in breads (17.69 to 102.71 µg/g), cookie (15.81 to 54.43 µg/g), and pasta (4.88 to 28.39 µg/g). Phenolic acid composition of whole wheat products appeared to be better estimated by digestion methods than the chemical extraction method. The unique insoluble-bound nature and fermentability of wheat phenolic acids may lead to a mechanistic understanding of whole grain consumption for potential colorectal cancer prevention.

Intracellular protein kinase CK2 inhibition by ferulic acid-based trimodal nanodevice.

Protein kinase CK2, a pleiotropic and constitutively active kinase, is strictly involved in different diseases, especially in cancer. Many efforts have been carried out to develop specific CK2 inhibitors and recently, it has been evidenced that ferulic acid (FA) represents a promising, albeit cell impermeable, CK2 inhibitor. In the present study, the potential of a nanotechnological approach to cope with intracellular CK2 regulation was explored. Surface-Active Maghemite Nanoparticles (SAMNs), coupling magnetism with photoluminescence, a new feature of SAMNs here described for the first time, were chosen as dual imaging nanocarrier for FA. The self-assembled nanodevice (SAMN@FA) displayed a significant CK2 inhibitory activity in vitro. Moreover, effective cellular internalization of SAMN@FA in cancer cells was proved by direct visualization of the photoluminescent nanocarrier by confocal microscopy and was corroborated by phosphorylation levels of endogenous CK2 targets. The proposed trimodal nanodevice, representing the first example of cellular CK2 nano-inhibition, paves the way for novel active nanocarriers as appealing theranostic tool for future biomedical applications.

Natural Sources, Pharmacokinetics, Biological Activities and Health Benefits of Hydroxycinnamic Acids and Their Metabolites.

Hydroxycinnamic acids (HCAs) are important natural phenolic compounds present in high concentrations in fruits, vegetables, cereals, coffee, tea and wine. Many health beneficial effects have been acknowledged in food products rich in HCAs; however, food processing, dietary intake, bioaccessibility and pharmacokinetics have a high impact on HCAs to reach the target tissue in order to exert their biological activities. In particular, metabolism is of high importance since HCAs' metabolites could either lose the activity or be even more potent compared to the parent compounds. In this review, natural sources and pharmacokinetic properties of HCAs and their esters are presented and discussed. The main focus is on their metabolism along with biological activities and health benefits. Special emphasis is given on specific effects of HCAs' metabolites in comparison with their parent compounds.

Experimental confounding factors affecting stability, transport and metabolism of flavanols and hydroxycinnamic acids in Caco-2 cells.

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.

Assessment of bioactive compounds and their in vitro bioaccessibility in whole-wheat flour pasta.

We studied the polyphenol profile and antioxidant properties of cooked whole-wheat pasta to evaluate its effective antioxidant capacity, including changes produced by its production and in vitro digestion. The polyphenol profile was studied by HPLC-ESI-MS/MS, while the antioxidant capacity was measured by TEAC and FRAP assays. Results show that the polyphenol profile and antioxidant capacity change along the elaboration of cooked pasta, being the cooking step important to increase the release of bound polyphenols, enhancing their antioxidant properties. On the other hand, the study of the bioaccessibility of polyphenols, using an experimental model that simulates human gastrointestinal digestion and subsequent absorption, showed that only a small fraction of the starting polyphenolic compounds, mainly free polyphenols, could be absorbed by the small intestine; thus, reducing their effective antioxidant capacity. To our knowledge, this is the first report showing the bioaccessibility of hydroxybenzoic acid glucoside, hydroxybenzoic acid diglucoside, tryptophan, 6-C-glucosyl-8-C-arabinosyl-apigenin and diferulic acids.

Phenolic Acids Derivatives - Biotechnological Methods of Synthesis and Bioactivity.

Phenolic acids are secondary plant metabolites belonging to polyphenol classes, widely spread throughout the plant kingdom. The name "phenolic acids", in general, describes phenols that possess one carboxylic acid functionality and they could be divided into three major subclasses: hydroxybenzoic, hydroxycinnamic and hydroxyphenylacetic acids. The great interest in phenolic acids is associated with their high potential for food preservation (antioxidant and antimicrobial activity) and, last but not least, high therapeutic potential. The aim of this review is to summarise the current knowledge concerning phenolic acids and the topics discussed include natural sources of phenolic acids, biosynthesis and metabolism, health benefits of phenolic acids (first of all the antioxidant activity of dietary phenolics and also anticarcinogenic and anti-inflammatory effect), their antimicrobial activity for selected groups of bacteria and fungi (yeasts) and structural modifications of the molecule especially those increasing lipophilicity and improving solubility in lipids. Recent advances in the methods of enzymatic synthesis of phenolic acid derivatives are described and some conclusions referring to Structure-Property-Activity Relationships of phenolic acids, particularly important from the point of view of their pharmaceutical and nutritional applications, are discussed.

Pharmacokinetic, Antiproliferative and Apoptotic Effects of Phenolic Acids in Human Colon Adenocarcinoma Cells Using In Vitro and In Silico Approaches.

Colon cancer is the second most common cause of cancer deaths in the USA and Europe. Despite aggressive therapies, many tumors are resistant to current treatment protocols and epidemiological data suggest that diet is a major factor in the etiology of colon cancer. This study aimed to evaluate the antioxidant activity and the influence of 3,4-dihydroxyphenylacetic (3,4-DHPAA), p-coumaric (p-CoA), vanillic (VA) and ferulic (FA) acids on cell viability, cell cycle progression, and rate of apoptosis in human colon adenocarcinoma cells (HT-29). The results showed that all compounds tested reduce cell viability in human colon cancer cells. 3,4-DHPAA promoted the highest effect antiproliferative with an increase in the percentage of cells in G0/G1 phase, accompanied by a reduction of cells in G2/M phase. Cell cycle analysis of VA and FA showed a decrease in the proportion of cells in G0/G1 phase (10.0 µM and 100.0 µM). p-CoA and FA acids increased the percentage of apoptotic cells and non-apoptotic cells. 3,4-DHPAA seems to be the substance with the greatest potential for in vivo studies, opening thus a series of perspectives on the use of these compounds in the prevention and treatment of colon cancer.

Application of TQSM polypharmacokinetics and its similarity approach to ascertain Q-marker by analyses of transitivity in vivo of five candidates in Buyanghuanwu injection.

BACKGROUND: It is well-known that the public still have been facing on a severe issue about the inconsistency of quality and therapeutic efficacy of traditional medicines. Recently, Professor Chang-Xiao Liu has created a new promising concept for identifying relevant quality-markers (Q-marker) from herbs, their formulas and manufacturing products. Therefore, building up a new approach is necessary for us to bridge over quality to efficacy of pharmaceutical products. STUDY DESIGN: In this paper, five candidate Q-markers, astragaloside IV, paeonflorin, amygdalin, tetramethylpyrazine, ferulic acid in Buyanghuanwu injection (BYHWI) had been designed to carry out in rat by using single and polypharmacokinetic models for total quanta to ascertain adequate Q-marker. METHODS: The Q-marker transitivity in vivo was studied with polypharmacokinetic model and its similarity approach, which were modeled with TQSM principle. The Q-marker was ascertained with transitive similarity and bioavailability in polypharmacokinetics. Their concentrations in plasma sample of white rat were determined by RP-HPLC. Data analyses were used by the DAS software for singles and myself-written-program with EXCEL for multiples. RESULTS: In BYHWI, five candidate Q-marker pharmacokinetic profiles were singly fixed to two compartmental models in rat using classical compartmental analysis, but there were tremendous differences among which the candidate parameters were fluctuated from nearly 3552 folds to equivalency. The theoretical value of TQSM polypharmacokinetic parameters such as AUCT, MRTT, VRTT, CLT, VT over the mixure of five drugs were 110.8 ±â€¯51.91 mg min ml-1, 176.0 ±â€¯36.5 min, 39,921 ±â€¯4311 min2, 0.3116 ±â€¯0.02347 ml min-1 kg-1, 54.83 ±â€¯7.683 ml kg-1 respectively. The TQSM polypharmacokinetic parameters in astragaloside Ⅳ ordered by AUCT, MRTT, VRTT, CLT, VT were 110.8 ±â€¯51.91 mg min ml-1, 176.0 ±â€¯36.5 min, 39,921 ±â€¯4311 min2, 0.3116 ±â€¯0.02347 ml min-1 kg-1, 54.83 ±â€¯7.683 ml kg-1, respectively, which were closed to the theoretical values. TQSM similarity versus astragaloside Ⅳ was 0.9661. CONCLUSION: The results represented that the optimum Q-marker in BYHWI is astragaloside Ⅳ, whose transitivity in vivo similarity was close to the behavior of polypharmacokinetics with maximum bioavailability to the total quanta. It is feasible for Q-marker in CMMs to screen on the comparison of single pharmacokinetic behavior and bioavailability to the total quanta.

[Effects of Frankincense and Myrrh essential oil on transdermal absorption of ferulic acid in Chuanxiong].

The aim of this paper was to explore the effects of Frankincense and Myrrh essential oil on transdermal absorption, and investigate the mechanism of permeation on the microstructure and molecular structure of stratum corneum. Through the determination of stratum corneum/medium partition coefficient of ferulicacid in Chuanxiong influenced by Frankincense and Myrrh essential oil, the effects of volatile oil of frankincense and Myrrh on the the microscopic and molecular structure of stratum corneum were explored by observation of skin stratum corneum structure under scanning electron microscopy, and investigation of frankincense and myrrh essential oil effects on the molecular structure of keratin and lipids in stratum corneum under Fourier transform infrared spectroscopy. The results showed that the oil could enhance the distribution of ferulic acid in the stratum corneum and medium, and to a certain extent damaged the imbricate structure of stratum corneum which was originally regularly, neatly, and closely arranged; some epidermal scales turned upward, with local peeling phenomenon. In addition, frankincense and myrrh essential oil caused the relative displacement of CH2 stretching vibration peak of stratum corneum lipids and amide stretching vibration peak of stratum corneum keratin, indicating that frankincense and myrrh essential oil may change the conformation of lipid and keratin in the stratum corneum, increase the bilayer liquidity of the stratum corneum lipid, and change the orderly and compact structure to increase the skin permeability and reduce the effect of barrier function. It can be concluded that Frankincense and Myrrh essential oil can promote the permeation effect by increasing the distribution of drugs in the stratum corneum and changing the structure of the stratum corneum.

Simultaneous determination of ferulic acid and gastrodin of Tianshu Capsule in rat plasma by ultra-fast liquid chromatography with tandem mass spectrometry and its application to a comparative pharmacokinetic study in normal and migraine rats.

Tianshu Capsule, consisting of Ligusticum chuanxiong Hort and Gastrodia elata Blume, is a widely used Traditional Chinese Medicine preparation for the treatment of migraine. Ferulic acid and gastrodin are main active constituents in Ligusticum chuanxiong Hort and Gastrodia elata Blume, and have been used as marker components for quality control of Tianshu Capsule. In this study, a selective, sensitive, and reliable ultra-fast liquid chromatography with tandem mass spectrometry method was developed for simultaneous determination of ferulic acid and gastrodin in rat plasma using geniposide as internal standard. The plasma samples were extracted by protein precipitation with methanol after acidification and separated on a Shim-Pack XR-ODS C18 column (75 × 3.0 mm, 2.2 µm) using gradient elution with a mobile phase consisting of water (containing 0.1% formic acid) and acetonitrile at a flow rate of 0.6 mL/min. Detection was performed on 3200 QTRAP mass spectrometry equipped with turbo ion spray source in negative ionization mode. Validation parameters were within acceptable ranges. The validated method was applied to compare the pharmacokinetic profiles of ferulic acid and gastrodin in normal and migraine rats. Our results showed that there were remarkable differences in the pharmacokinetic properties of the analytes between the normal and migraine groups.

New insights into the ameliorative effects of ferulic acid in pathophysiological conditions.

Ferulic acid, a natural phytochemical has gained importance as a potential therapeutic agent by virtue of its easy commercial availability, low cost and minimal side-effects. It is a derivative of curcumin and possesses the necessary pharmacokinetic properties to be retained in the general circulation for several hours. The therapeutic effects of ferulic acid are mediated through its antioxidant and anti-inflammatory properties. It exhibits different biological activities such as anti-inflammatory, anti-apoptotic, anti-carcinogenic, anti-diabetic, hepatoprotective, cardioprotective, neuroprotective actions, etc. The current review addresses its therapeutic effects under different pathophysiological conditions (eg. cancer, cardiomyopathy, skin disorders, brain disorders, viral infections, diabetes etc.).

Bioavailability of tomato polyphenols is enhanced by processing and fat addition: Evidence from a randomized feeding trial.

SCOPE: Tomato contains a variety of phenolics associated with health-promoting properties. However, the effects of processing and the addition of oil during tomato sauce preparation on microbial metabolism of phenolics in the small intestine are still unclear. METHODS AND RESULTS: An open, controlled, randomized, and crossover feeding trial with 40 healthy volunteers was carried out to analyze the metabolites in plasma and urine after the consumption of tomato and tomato sauces, with tomato sauce enriched with refined olive oil (ROOE) and without refined olive oil (oil-free: OF). Ten phenolics in plasma and 93 metabolites in urine were quantified. Processing tomatoes into sauce enhanced the bioavailability of flavanones, flavanols, and some hydroxycinnamic acids, as reflected by the increase in the area under the plasma concentration versus time curve. An increase in their plasma half-life was also observed, particularly after ingestion of ROOE, possibly favored by enterohepatic circulation. A wide variety of gut microbial metabolites was also detected, namely flavanones, hydroxycinnamic acids, flavonols, hydroxyphenylpropanoic acids, hydroxyphenylacetic acids, and hydroxybenzoic acids. CONCLUSIONS: Flavanones and flavonols in ROOE presented higher bioavailability, suggesting that the processing undergone by the raw tomato improved their absorption.

Bioavailability of Alfrutamide and Caffedymine and Their P-Selectin Suppression and Platelet-Leukocyte Aggregation Mechanisms in Mice.

BACKGROUND: Alfrutamide and caffedymine are phenolic amides found in plants, including garlic and cocoa. However, the bioavailability of alfrutamide and caffedymine and their effects on cardiovascular diseases (CVDs), particularly via effects on P-selectin expression(PSE) and platelet-leukocyte aggregation (PLA), are unknown. OBJECTIVE: The objective of this study was to investigate the bioavailability of alfrutamide and caffedymine and their effects on PSE and PLA, which are frequently involved in the progression of CVDs. METHODS: Cyclooxygenase (COX) I and COX-II activities and cAMP were determined by using COX and cAMP kits. Bioavailability was determined by HPLC analysis of plasma samples from Swiss Webster mice orally administered alfrutamide and caffedymine (10 µg each). PSE and PLA were also measured by flow cytometry using blood samples from the same mice. RESULTS: At 0.05 µmol/L, alfrutamide and caffedymine inhibited COX-I and COX-II by 20-40% (P < 0.05) and 16-33% (P < 0.05), respectively, compared with the control. At 0.1 µmol/L, the 2 compounds also inhibited platelet PSE by 28% (P < 0.05) and 35% (P < 0.05), respectively, compared with the control. The ß2-adrenoceptor antagonists ICI118551 and butoxamine partially suppressed the inhibition of PSE by caffedymine, suggesting that ß2 receptors are involved in inhibition by caffedymine but not by alfrutamide. At the same concentration (0.1 µmol/L), however, these 2 compounds inhibited PLA by 24-32% (P < 0.05) compared with the control. In addition, mice administered caffedymine and alfrutamide orally (10 µg/35 g body weight) exhibited maximum concentrations >0.6 µmol/L and significant inhibition of PSE by 23-34% (P < 0.05) and PLA by 20-27% (P < 0.05) compared with control mice. CONCLUSIONS: These data show the adequate bioavailability of alfrutamide and caffedymine and their different mechanisms of suppressing PSE and PLA: alfrutamide exerts its effects only via COX inhibition, whereas caffedymine works through both COX inhibition and cAMP amplification.

Systematic analysis of the polyphenol metabolome using the Phenol-Explorer database.

SCOPE: The Phenol-Explorer web database details 383 polyphenol metabolites identified in human and animal biofluids from 221 publications. Here, we exploit these data to characterize and visualize the polyphenol metabolome, the set of all metabolites derived from phenolic food components. METHODS AND RESULTS: Qualitative and quantitative data on 383 polyphenol metabolites as described in 424 human and animal intervention studies were systematically analyzed. Of these metabolites, 301 were identified without prior enzymatic hydrolysis of biofluids, and included glucuronide and sulfate esters, glycosides, aglycones, and O-methyl ethers. Around one-third of these compounds are also known as food constituents and corresponded to polyphenols absorbed without further metabolism. Many ring-cleavage metabolites formed by gut microbiota were noted, mostly derived from hydroxycinnamates, flavanols, and flavonols. Median maximum plasma concentrations (C(max)) of all human metabolites were 0.09 and 0.32 µM when consumed from foods or dietary supplements, respectively. Median time to reach maximum plasma concentration in humans (T(max)) was 2.18 h. CONCLUSION: These data show the complexity of the polyphenol metabolome and the need to take into account biotransformations to understand in vivo bioactivities and the role of dietary polyphenols in health and disease.

Polyphenols from artichoke heads (Cynara cardunculus (L.) subsp. scolymus Hayek): in vitro bio-accessibility, intestinal uptake and bioavailability.

Artichoke is a rich source of health promoting compounds such as polyphenols, important for their pharmaceutical and nutritional properties. In this study, the potential for bioavailability of the artichoke polyphenols was estimated by using both in vitro digestion and Caco-2 human intestinal cell models. In vitro digestive recoveries (bio-accessibility) were found to be 55.8% for total artichoke phenolics and in particular, 70.0% for chlorogenic acid, 41.3% for 3,5-O-dicaffeoylquinic acid, and 50.3% for 1,5-O-dicaffeoylquinic acid, highlighting potential sensitivity of these compounds to gastric and small intestinal digestive conditions. Uptake of artichoke polyphenols was rapid with peak accumulation occurring after 30 min with an efficiency of 0.16%, according to the poor uptake of dietary polyphenols. Some compounds, such as coumaric acid, caffeic acid and caffeic acid derivatives, were also detected in the basolateral side assuming extra and intracellular esterase activities on chlorogenic acid. Only apigenin-7-O-glucoside was transported through the Caco-2 monolayer demonstrating its bioavailability to the extent of 1.15% at 60 min. In addition, permeability coefficient (Papp = 2.29 × 10(-5) cm s(-1)), involving apical to basolateral transport of apigenin 7-O-glucoside, was calculated to facilitate estimation of transport through the Caco-2 monolayer. Finally, the mono and dicaffeoylquinic acids present in artichoke heads exert an antioxidant activity on the human low density lipoprotein system correlated to their chemical structure. In conclusion, the utilized in vitro models, although not fully responding to the morphological and physiological features of human in vivo conditions, could be a useful tool for investigating mechanistic effects of polyphenols released from the food matrix.

Novel tacrine-grafted Ugi adducts as multipotent anti-Alzheimer drugs: a synthetic renewal in tacrine-ferulic acid hybrids.

Herein we describe the design, multicomponent synthesis, and biological, molecular modeling and ADMET studies, as well as in vitro PAMPA-blood-brain barrier (BBB) analysis of new tacrine-ferulic acid hybrids (TFAHs). We identified (E)-3-(hydroxy-3-methoxyphenyl)-N-{8[(7-methoxy-1,2,3,4-tetrahydroacridin-9-yl)amino]octyl}-N-[2-(naphthalen-2-ylamino)2-oxoethyl]acrylamide (TFAH 10 n) as a particularly interesting multipotent compound that shows moderate and completely selective inhibition of human butyrylcholinesterase (IC50 =68.2 nM), strong antioxidant activity (4.29 equiv trolox in an oxygen radical absorbance capacity (ORAC) assay), and good ß-amyloid (Aß) anti-aggregation properties (65.6 % at 1:1 ratio); moreover, it is able to permeate central nervous system (CNS) tissues, as determined by PAMPA-BBB assay. Notably, even when tested at very high concentrations, TFAH 10 n easily surpasses the other TFAHs in hepatotoxicity profiling (59.4 % cell viability at 1000 µM), affording good neuroprotection against toxic insults such as Aß1-40 , Aß1-42 , H2 O2 , and oligomycin A/rotenone on SH-SY5Y cells, at 1 µM. The results reported herein support the development of new multipotent TFAH derivatives as potential drugs for the treatment of Alzheimer's disease.

In vitro colonic catabolism of orange juice (poly)phenols.

SCOPE: The role of colonic microbiota in the breakdown of hesperetin, naringenin, and ferulic acid, compounds found as glycosides in orange juice, was investigated using an in vitro fermentation model. METHODS AND RESULTS: Test compounds were incubated with human fecal slurries cultured under anaerobic conditions, and the production of phenolic acid catabolites were monitored by GC-MS and HPLC-MS(2) . Hesperetin was converted to 3-(3'-hydroxy-4'-methoxyphenyl)propionic acid, 3-(3',4'-dihydroxyphenyl)propionic acid, and 3-(3'-hydroxyphenyl)propionic acid while 3-(phenyl)propionic acid was the major end product derived from naringenin. The data obtained are compared to our previously published data on urinary excretion of phenolic and aromatic acids after acute orange juice consumption (Pereira-Caro et al. Am. J. Clin. Nutr. 2014, 100, 1385-1391). Catabolism pathways are proposed for events occurring in the colon and those taking place postabsorption into the circulatory system with particular reference to the excretion of 3-(3'-hydroxy-4'-methoxyphenyl)hydracrylic acid, which is not formed in fecal incubations. Ferulic acid was also degraded by the colonic microflora being converted principally to 3-(3'-methoxy-4'-hydroxyphenyl)propionic acid, a phenolic acid that appears in urine after orange juice consumption. CONCLUSION: The study provides novel information on the potential involvement of the colonic microbiota in the overall bioavailability of orange juice (poly)phenols through the production of phenylpropionic acids and subsequent hepatic conversions that lead to hippuric acid and its hydroxylated analogues.

The abundant dietary constituent ferulic acid forms a wide range of metabolites including a glutathione adduct when incubated with rat hepatocytes.

1. The metabolism of ferulic acid (FA) has been studied in a number of different systems and several metabolites of FA have been characterised. No previous work has been carried out using hepatocytes to characterise the metabolism of FA. 2. A metabolomics approach in combination with high resolution mass spectrometry was used to characterise the metabolites of FA formed in isolated rat hepatocytes. FA was incubated with rat hepatocytes and the metabolites formed were profiled at 30 and 120 minutes. The metabolites were characterised according to their accurate mass at <2 ppm using Fourier transform mass spectrometry (FT-MS). 3. Sixteen metabolites of FA were identified. The most abundant metabolite was the sulphate of FA and this was followed by FA glucuronide and glycine conjugates. A wide range of low level metabolites were produced in the hepatocyte incubations. Novel metabolites resulted from side chain oxidation. 4. In addition, a glutathione (GSH) adduct of FA was formed. Incubation of a solution of FA with GSH also resulted in formation of this adduct indicating that it could be formed purely by a chemical reaction. Thus the metabolism of FA in rat hepatocytes is more complex than previously described.