Heteroconjugates of quercetin with 4'-O-sulfate selectively accumulate in rat plasma due to limited urinary excretion.

Quercetin and methylquercetin are present in a variety of sulfate and glucuronide conjugates in the plasma of quercetin-fed rats and humans. Quercetin conjugates exhibit various physiological activities, depending on the type and position of conjugation. However, little is known regarding the type and position of isomers of quercetin conjugates in the plasma, their accumulation in the liver and kidneys, and their excretion via urine. Using authentic standards of quercetin conjugates and liquid chromatography-tandem mass spectrometry (LC/MS/MS) analysis, we identified and quantified various quercetin conjugates in blood plasma, urine, liver, and kidney tissues 1, 4, and 10 h after orally administering 33.1 µmol kg-1 quercetin glucosides to rats. The profiles of quercetin conjugates were largely different among plasma, urine, liver, and kidneys. Very limited heteroconjugates (7-O-glucuronide-4'-O-sulfate) of quercetin and methylquercetin dominated in the plasma, but these heteroconjugates were much less excreted via urine and did not largely accumulate in the liver and kidneys. Heteroconjugates constituting sulfates other than 4' position sulfate, 7-O-glucuronide-3'-O-sulfate, 4'-O-glucuronide-7-O-sulfate, and 3'-O-glucuronide-7-O-sulfate were major metabolites in urine, but were minimally detected in the plasma. We also found that mono-sulfate conjugates were abundant in the liver and renal tissues. These results suggest that excretion of quercetin conjugates, especially heteroconjugates, into urine is highly selective. The heteroconjugates with 4'-O-sulfate may be scarcely excreted via urine, and thus accumulate in the blood plasma. Further research is necessary to evaluate the physiological effects of heteroconjugates accumulated in the plasma.

Effect of Lipopolysaccharide-Induced Inflammatory Challenge on ß-Glucuronidase Activity and the Concentration of Quercetin and Its Metabolites in the Choroid Plexus, Blood Plasma and Cerebrospinal Fluid.

Quercetin-3-glucuronide (Q3GA), the main phase II metabolite of quercetin (Q) in human plasma, is considered to be a more stable form of Q for transport with the bloodstream to tissues, where it can be potentially deconjugated by ß-glucuronidase (ß-Gluc) to Q aglycone, which easily enters the brain. This study evaluates the effect of lipopolysaccharide (LPS)-induced acute inflammation on ß-Gluc gene expression in the choroid plexus (ChP) and its activity in blood plasma, ChP and cerebrospinal fluid (CSF), and the concentration of Q and its phase II metabolites in blood plasma and CSF. Studies were performed on saline- and LPS-treated adult ewes (n = 40) receiving Q3GA intravenously (n = 16) and on primary rat ChP epithelial cells and human ChP epithelial papilloma cells. We observed that acute inflammation stimulated ß-Gluc activity in the ChP and blood plasma, but not in ChP epithelial cells and CSF, and did not affect Q and its phase II metabolite concentrations in plasma and CSF, except Q3GA, for which the plasma concentration was higher 30 min after administration (p < 0.05) in LPS- compared to saline-treated ewes. The lack of Q3GA deconjugation in the ChP observed under physiological and acute inflammatory conditions, however, does not exclude its possible role in the course of neurodegenerative diseases.

Untargeted metabolomics reveals the mechanism of quercetin enhancing the bioavailability of ticagrelor.

Ticagrelor is a first-line clinical drug for the treatment of acute coronary syndrome, but its oral bioavailability is relatively low. Flavonoids (polyphenol compounds commonly found in plant foods) seriously affect human metabolism and health. This study compared the effects of quercetin, luteolin and catechin on the pharmacokinetic parameters of ticagrelor and found that quercetin can significantly increase the Cmax and area under the curve from time zero to 36 h (AUC0-36 ) of ticagrelor, that is, quercetin can enhance the bioavailability of ticagrelor, but luteolin and catechin cannot. The difference between the ticagrelor group and the combination of quercetin and ticagrelor was analyzed through untargeted metabolomics methods and multivariate data analysis, which identified changes in the levels of seven metabolites (deoxycholic acid, taurocholic acid, glycocholic acid, glycoursodeoxycholic acid, tryptophan, phenylalanine and kynurenine). Based on the changes of these metabolites, we found that the metabolic pathways of phenylalanine, tyrosine and tryptophan and the biosynthetic pathway of bile acids were changed. A metabolomics study revealed that quercetin improves the oral bioavailability of ticagrelor and that this might rely on changing the metabolic pathways of phenylalanine, tyrosine and tryptophan and the biosynthetic pathway of bile acids. The research results at the metabolic level provide us with a strong basis and direction for further exploring the mechanism underlying quercetin's ability to enhance the bioavailability of ticagrelor, and this may be useful for finding new agents that enhance the bioavailability.

Rp-HPLC Determination of Quercetin in a Novel D-α-Tocopherol Polyethylene Glycol 1000 Succinate Based SNEDDS Formulation: Pharmacokinetics in Rat Plasma.

Despite its proven efficacy in diverse metabolic disorders, quercetin (QU) for clinical use is still limited because of its low bioavailability. D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) is approved as a safe pharmaceutical adjuvant with marked antioxidant and anti-inflammatory activities. In the current study, several QU-loaded self-nanoemulsifying drug delivery systems (SNEDDS) were investigated to improve QU bioavailability. A reversed phase high performance liquid chromatography (RP-HPLC) method was developed, for the first time, as a simple and sensitive technique for pharmacokinetic studies of QU in the presence of TPGS SNEDDS formula in rat plasma. The analyses were performed on a Xterra C18 column (4.6 × 100 mm, 5 µm) and UV detection at 280 nm. The analytes were separated by a gradient system of methanol and phosphate buffer of pH 3. The developed RP-HPLC method showed low limit of detection (LODs) of 7.65 and 22.09 ng/mL and LOQs of 23.19 and 66.96 ng/mL for QU and TPGS, respectively, which allowed their determination in real rat plasma samples. The method was linear over a wide range, (30-10,000) and (100-10,000) ng/mL for QU and TPGS, respectively. The selected SNEDDS formula, containing 50% w/w TPGS, 30% polyethylene glycol 200 (PEG 200), and 20% w/w pumpkin seed oil (PSO), showed a globule size of 320 nm and -28.6 mV zeta potential. Results of the pharmacokinetic studies showed 149.8% improvement in bioavailability of QU in SNEDDS relative to its suspension. The developed HPLC method proved to be simple and sensitive for QU and TPGS simultaneous determination in rat plasma after oral administration of the new SNEDDS formula.

Simple and Efficient Detection Approach of Quercetin from Biological Matrix by Novel Surface Imprinted Polymer Based Magnetic Halloysite Nanotubes Prepared by a Sol-Gel Method.

Molecular imprinted polymers coated magnetic halloysite nanotubes (MHNTs-MIPs) were prepared through sol-gel method by using quercetin (Que), APTES and TEOS as template, monomer and cross-linker agent, respectively. The synthesized MHNTs-MIPs were characterized by fourier transform infrared, scanning electron microscope, transmission electron microscope, XRD and vibrating sample magnetometer. Various parameters influencing the binding capacity of the MHNTs-MIPs were investigated with the help of response surface methodology. Selectivity experiments showed that the MHNTs-MIPs exhibited the maximum selective rebinding to Que. Therefore, the MHNTs-MIPs was applied as a solid-phase extraction adsorbent for the extraction and preconcentration of quercetin and luteolin in serum and urine samples. The limits of detection for quercetin and luteolin range from 0.51 to 1.32 ng mL-1 in serum and from 0.23 to 1.05 ng mL-1 in urine, the recoveries are between 95.20 and 103.73% with the RSD less than 5.77%. While the recovery hardly decreased after several cycles. The designed MHNTs-MIP with high affinity, sensitivity and maximum selectivity toward Que in SPE might recommend a novel method for the extraction of flavonoids in other samples like natural products.

Gold nanoparticle-graphene quantum dots nanozyme for the wide range and sensitive electrochemical determination of quercetin in plasma droplets.

A gold nanoparticle/graphene quantum dots (AuNP/GQD) nanozyme-modified screen-printed carbon electrode (SPCE) was developed for fast and ultrasensitive determination of quercetin by square-wave voltammetry. The nanosensing device was inserted in miniaturized equipment. Under the optimal experimental conditions, a good linear relationship between oxidation peak current and concentration of quercetin within a very wide range of 1.0 × 10-10 to 1.0 × 10-3 mol L-1 was obtained, with a very low limit of detection of 3.3 × 10-11 mol L-1. To prove the performance of the method, the reproducibility was evaluated and the RSD values were lower than 5.3% and 5.1% for the intra-day and inter-day measurements, respectively. The method was applied to the sensitive determination of quercetin in human plasma droplets with recovery rates of 92.6 to 101.7%.Graphical abstract.

Quercetin improves gut dysbiosis in antibiotic-treated mice.

The diversity and activity of the gut microbiota residing in humans and animals are significantly influenced by the diet. Quercetin, one of the representative polyphenols in human diets, possesses a wide range of biological properties. The aim of this study was to investigate the prebiotic effects of quercetin in antibiotic-treated mice. Gut dysbiosis was successfully induced in mice by treatment with an antibiotic cocktail. Gas chromatography and 16S rDNA high-throughput sequencing techniques were used to investigate short-chain fatty acid content and gut microbial diversity and composition. The results showed that quercetin supplementation significantly improved the diversity of the gut bacterial community in antibiotic-treated mice (P < 0.05). Meanwhile, intestinal barrier function was also recovered remarkably as indicated by a decrease in the content of serum d-lactic acid and the activity of serum diamine oxidase (P < 0.05). The length of intestinal villi and mucosal thickness were also significantly increased in response to quercetin treatment (P < 0.05). Furthermore, the production of butyrate in faeces was enhanced significantly in quercetin-treated mice (P < 0.05). In conclusion, quercetin is effective in recovering gut microbiota in mice after antibiotic treatment and may act as a prebiotic in combatting gut dysbiosis.

Brain delivery of quercetin-loaded exosomes improved cognitive function in AD mice by inhibiting phosphorylated tau-mediated neurofibrillary tangles.

It is reported that quercetin (Que) can prevent tau pathology and induce neuroprotection by improving cognitive and functional symptoms in the treatment of Alzheimer's disease (AD). However, its clinical application has been limited due to its poor brain targeting and bioavailability. Exosomes are considered as cargo carriers for intercellular communication and especially serve as a natural and important drug brain delivery platform for achieving better treatment of central neurological diseases. Here, we developed plasma exosomes (Exo) loaded with Que (Exo-Que) to improve the drug bioavailability, enhance the brain targeting of Que and potently ameliorate cognitive dysfunction in okadaic acid (OA)-induced AD mice. Our results showed that Exo-Que improved brain targeting of Que as well as significantly enhanced bioavailability of Que. Furthermore, compared with free Que, Exo-Que better relieved the symptoms of AD by inhibiting cyclin-dependent kinase 5 (CDK5)-mediated phosphorylation of Tau and reducing formation of insoluble neurofibrillary tangles (NFTs), suggesting its therapeutic potential for better treatment of AD.

Rapid synthesis of multifunctional carbon nanodots as effective antioxidants, antibacterial agents, and quercetin nanoprobes.

A facile and rapid synthesis of multifunctional carbon nanodots (CNDs) was developed by using the acid-base neutralization spontaneous heat with glucose as precursor, 1,2-ethylenediamine (EDA) and concentrated nitric acid as dual N-dopants. The CND has a tremendous antioxidant potency, which represents effective inhibitory concentrations of reactive oxygen species that are significantly lower than ascorbic acid. Furthermore, minimum inhibitory concentration (MIC) assay revealed CNDs possessed significant antimicrobial activity for Gram-positive S. aureus and Gram-negative E. coli. Moreover, the CNDs are endowed with favorable fluorescence (FL) behaviors including the quantum yield (QY) of 14.2% and stable FL within a wide range of pH and high tolerance to external ionic strength, rendering them applicable in quercetin (QCT) detection as a FL nanoprobe. The CNDs were effectively quenched by QCT due to static quenching which takes place by the electrostatic interaction between basic groups of CNDs and QCT of 3-hydroxyl. This nanoprobe had profitable selectivity and sensitivity towards QCT with a linearity ranging from 1 µM to 47 µM and a low detection limit of 172.4 nM and were successfully performed for QCT detection in human serum and urine samples.

Magnetic molecularly imprinted polymer combined with high performance liquid chromatography for selective extraction and determination of the metabolic content of quercetin in rat plasma.

In this study, a novel magnetic solid phase extraction adsorbent was prepared, namely Fe3O4@SiO2 as the carrier, quercetin as the template molecule, acrylamide (AM) as the functional monomer, ethylene glycol dimethacrylamide (EGDMA) as the crosslinker, 2,2'-azobisisobutyronitrile (AIBN) as the initiator to prepare magnetic molecularly imprinted polymer (MMIPs) with specific adsorption of quercetin by surface molecular imprinting technique. MMIPs were characterized by Fourier transform infrared spectrometer (FT-IR), X-ray diffraction (XRD) and transmission electron microscope (TEM). The binding properties of MMIPs were evaluated by isothermal adsorption, kinetic adsorption and selective adsorption experiments. The results showed that the saturated adsorption capacity and adsorption time were 17.9 µmol/g and 20 min, respectively, and showed high selectivity for quercetin. Under optimized conditions, the limit of detection (LOD) and limit of quantitation (LOQ) were 55.327 ng/mL and 184.413 ng/mL, respectively. The recovery and RSD were 85.34-95.67% and 3.36-6.59, respectively. We successfully combined magnetic solid phase extraction with high performance liquid chromatography (MSPE-HPLC-UV) for the enrichment, separation and detection of quercetin in rat plasma. The results showed that the peak and half-life of quercetin in plasma were 1.5 h (32.310 µg/mL) and 3 h, respectively. The method was simple, rapid and efficient, and could be applied to the separation and detection of quercetin in complex matrices, and also provides a basis for the separation and identification of other natural chemical components.

High resolution UPLC-MS/MS method for simultaneous separation and determination of six flavonoids from semen cuscutae extract in rat plasma: application to comparative pharmacokinetic studies in normal and kidney-deficient rats.

Semen Cuscutae, which mainly consisted of flavonoids, is a traditional Chinese herbal medicine and used for nourishing the liver and kidneys. The aim of this study was to develop a sensitive and selective UPLC-MS/MS method for simultaneous separation and determination of six main active renoprotective components of Hyperoside, Astragalin, Isoquercitrin, Quercitrin, Quercetin, and Kaempferol from Semen Cuscutae in rat plasma, and to reveal the pharmacokinetic differences between normal and kidney deficient rats. The validated method has been successfully applied to comparing pharmacokinetic profiles of the six analytes in rat plasma. The results indicated that there was significant difference in pharmacokinetic parameters of the six analytes between two groups, while absorptions in kidney deficient group were significantly lower than those in normal group. This study would be helpful for evaluating the Semen Cuscutae as renoprotective drug candidates for pre-clinical and clinical research.

Plasma metabolomics analysis of endogenous and exogenous metabolites in the rat after administration of Lonicerae Japonicae Flos.

Lonicerae Japonicae Flos (LJF) is a typical herbal medicine and is used as a functional food. LJF, which has complex chemical compounds, has various biological effects. The global metabolomics, focusing on both the endogenous and exogenous metabolites, have not yet been investigated for LJF in normal healthy rats using LC-MS. In this study, plasma metabolomics was analyzed after the administration of LJF at different time intervals, and the exogenous metabolites were identified. Partial least squares discriminant analysis showed significant differences in chemical content in the dosed rats. Cholic acid, indoleacrylic acid, indolelactic acid, hippuric acid, N-acetyl-phenylalanine, and N-acetyl-serotonin significantly accumulated in the dosed rats. Lysophosphatidylethanolamine and lysophosphatidylcholine content, including plasmalogen, increased. There were 25 components of LJF, including 15 prototypes and 10 metabolites, that were identified. The 15 prototypes included phenolic acids, flavonoids, and iridoids, and their contents decreased with an increase in the administration time. Glucuronidation and sulfation of polyphenols were found for LJF. The exogenous glucuronide and sulfate metabolites-including dihydrocoumaric acid-sulfate, dihydrocaffeic acid-sulfate, dihydroferulic acid-sulfate, apigenin-glucuronide, apigenin-glucuronide-sulfate, isorhamnetin-glucuronide-sulfate, and others-were identified with a neutral loss of 176 and 80, respectively. The metabolic differences found in the study may serve as biomarkers of LJF consumption and promote the understanding of the mechanism of action of LJF.

A comparison of the absorption and metabolism of the major quercetin in brassica, quercetin-3-O-sophoroside, to that of quercetin aglycone, in rats.

Although flavonoid sophorosides are common glycosides in brassica vegetables, red raspberries and other food plants, there is a lack of studies of absorption and metabolism of any sophoroside. The aim of this study was to characterize the absorption, phase II metabolism and microbial catabolism of quercetin-3-O-sophoroside, compared to that of quercetin aglycone. Quercetin-3-O-sophoroside was purified from Apocynum venetum and characterized by MS2, 1H and 13C NMR. Using an in situ rat gut model, we found intact, methylated, sulfated and both methylated and sulfated quercetin sophoroside in the plasma following jejunal introduction of the sophoroside; we found derivatives of benzoic acid, phenylacetic acid, and phenyl propionic acid in the cecal contents following cecal introduction. This novel finding, that quercetin sophoroside was absorbed intact, without deglycosylation, points to a possible role for the terminal sugar and/or the type of linkage among glycosidic moieties in the mechanism of absorption of flavonoid glycosides.

One-step solvothermal synthesis of nanoflake-nanorod WS2 hybrid for non-enzymatic detection of uric acid and quercetin in blood serum.

Herein, we report a novel, one-step solvothermal assisted thermal decomposition synthesis of nanoflake-nanorod tungsten disulphide (WS2) nanomaterial and its application for non-enzymatic electrochemical sensing of uric acid (UA) and quercetin. The as-synthesised WS2 was characterized using X-ray diffraction (XRD), Raman spectrometer, Fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM). SEM analysis revealed the growth of 2D-1D nanoflake-nanorod hybrid nanostructure of 2H phase WS2 with greater defects and metal edges. Under optimized conditions, the WS2 modified glassy carbon electrode (WS2/GCE) facilitated the effective sensing of UA and quercetin which was measured using differential pulse voltammetry (DPV) technique. The sensor exhibited a low limit of detection (LoD) of 1.2 µM, the sensitivity of 312 nA/µM.cm2 for the dynamic range from 5 µM to 1 mM towards UA while an even lower of 2.4 nM and sensitivity of 258 nA/nM cm2 in the dynamic range of 10 nM-50 µM for quercetin. The enhanced sensing ability of the sensor attributed towards the synergetic effect of 2D-1D hybrid structure of WS2, wherein the 2D nanoflakes enhance the electrocatalytic property of WS2 with shorter diffusion length and 1D nanorods offer large surface area which provides greater number of active sites for sensing. Further, the sensor showed a remarkable selectivity towards UA and quercetin in the presence of ascorbic acid (AA), dopamine (DA), sodium (Na+), chloride (Cl-), calcium (Ca2+) and glucose. The sensor was further employed in successful detection of UA and quercetin in the simulated blood serum sample with excellent recovery percentages. The proposed synthesis route can be used to develop WS2 based electrochemical sensing platforms useful for various bioanalytical applications.

Comprehensive Analyses of Quercetin Conjugates by LC/MS/MS Revealed That Isorhamnetin-7- O-glucuronide-4'- O-sulfate Is a Major Metabolite in Plasma of Rats Fed with Quercetin Glucosides.

Quercetin glycosides in the diet are absorbed and converted to glucuronides, sulfates, or mixed conjugates of glucuronide and sulfate in plasma. Physiological effects of quercetin conjugates (Q-conjugates) differ depending on the type and position of conjugation. We developed a comprehensive analysis of Q-conjugates, including mixed conjugates, by LC/MS/MS. The whole species of Q-conjugates in tail blood plasma was measured on days 1, 3, and 12 in rats fed a 0.24% quercetin glucoside-containing diet. Twenty-three Q-conjugate molecules were detected, and 16 Q-conjugates among these were quantified using standard compounds. The most abundant metabolite in the plasma was mixed conjugates, comprising isorhamnetin-7- O-glucuronide-4'- O-sulfate, followed by quercetin-7- O-glucuronide-4'- O-sulfate; together, they accounted for 86% of total Q-conjugates on day 12. The profile of quercetin conjugate species did not significantly change during 12 days. The total Q-conjugate molecules quantified by our method was comparable with the total Q-conjugates quantified using an enzymatic deconjugation method.

Excitation-independent emission carbon nanoribbon polymer as a ratiometric photoluminescent probe for highly selective and sensitive detection of quercetin.

In this study, sulfur-nitrogen co-doped carbon nanoribbon (SNCNR) polymers with stable dual-emission fluorescence were synthesized using a one-step traditional hydrothermal method of 6-mercaptopurine in an aqueous methanol solution. Unexpectedly, the as-prepared SNCNRs with excitation-independent emission, as carbon nanomaterial derivatives, showed stable dispersions of a reticular-like shape and different lengths in the skeleton diameter. Compared with other carbon nanomaterials, the SNCNRs dramatically improved the electronic properties and surface chemical reactivities, and exhibited a sensitive ratiometric response to quercetin (Que) because of the Meisenheimer-like complexes formed through π-π stacking and electrostatic interaction. By using this SNCNR sensor, excellent ratiometric linear relationships (FL345 nm/FL420 nm) existed between the degree of quenching of the SNCNRs and the concentrations of Que in the range of 50.0 nM to 200 µM, and the limit of detection was 21.13 nM (3σ/k). Meanwhile, this sensor shows high selectivity for Que over other biomolecules, most amino acids and metal ions under the same conditions. Finally, this fluorescent probe was successfully applied to the direct analysis of Que in bovine serum and some beverage samples, which showed that it has potential for use in applications in clinical diagnosis and food analysis, and may pave the way for the design of effective fluorescent probes for other biologically related targets and food protection.

Quercetin and its metabolite isorhamnetin promote glucose uptake through different signalling pathways in myotubes.

Quercetin and its metabolite isorhamnetin elicit various beneficial effects on human health. However, their bioavailability is low. In this study, we investigated whether low concentrations in the physiological range could promote glucose uptake in L6 myotubes, as well as the underlying molecular mechanisms. We found that 0.1 nM and 1 nM quercetin or 1 nM isorhamnetin significantly increased glucose uptake via translocation of glucose transporter type 4 (GLUT4) to the plasma membrane of L6 myotubes. Quercetin principally activated the CaMKKß/AMPK signalling pathway at these concentrations, but also activated IRS1/PI3K/Akt signalling at 10 nM. In contrast, 1 nM and 10 nM isorhamnetin principally activated the JAK/STAT pathway. Treatment with siAMPKα and siJAK2 abolished quercetin- and isorhamnetin-induced GLUT4 translocation, respectively. However, treatment with siJAK3 did not affect isorhamnetin-induced GLUT4 translocation, indicating that isorhamnetin induced GLUT4 translocation mainly through JAK2, but not JAK3, signalling. Thus, quercetin preferably activated the AMPK pathway and, accordingly, stimulated IRS1/PI3K/Akt signalling, while isorhamnetin activated the JAK2/STAT pathway. Furthermore, after oral administration of quercetin glycoside at 10 and 100 mg/kg body weight significantly induced GLUT4 translocation to the plasma membrane of skeletal muscles in mice. In the same animals, plasma concentrations of quercetin aglycone form were 4.95 and 6.80 nM, respectively. In conclusion, at low-concentration ranges, quercetin and isorhamnetin promote glucose uptake by increasing GLUT4 translocation via different signalling pathways in skeletal muscle cells; thus, these compounds may possess beneficial functions for maintaining glucose homeostasis by preventing hyperglycaemia at physiological concentrations.

Bioavailability of Quercetin from Onion Extracts after Intraruminal Application in Cows.

The aim of the present study was to investigate the bioavailability of quercetin from onion bulb (OB) and onion skin (OS) extracts in ruminants. Three non-lactating cows equipped with a permanent rumen fistula intraruminally received equimolar amounts of quercetin as either aglycone, rutin, or OB or OS extract, respectively, at a dose of 50 mg of quercetin equivalents/kg of body weight. Blood samples were drawn before and frequently within the 24 h period after application of the respective substance. Quercetin and quercetin metabolites with an intact flavonol structure (kaempferol, isorhamnetin, and tamarixetin) were analyzed in plasma samples by high-performance liquid chromatography with fluorescence detection. All quercetin sources administered resulted in a fast increase of the plasma concentrations of quercetin and total flavonols (sum of quercetin and its metabolites), followed by a rapid decline, whereby significant higher concentrations occurred with OB extract and rutin compared to quercetin aglycone and OS extract, respectively. The results clearly demonstrate a higher systemic availability of quercetin from OB extract and rutin. Taken together, OB extract with a high content of quercetin glucosides is an interesting source for the application of quercetin to ruminants.

Simultaneous collection of the portal and superior vena cava blood in conscious rats defined that intestinal epithelium is the major site of glucuronidation, but not sulfation and methylation, of quercetin.

Quercetin is a flavonoid with many physiological effects. Absorbed quercetin is rapidly conjugated in the intestinal epithelium and liver. Different positional isomers of quercetin conjugates have different physiological properties. However, the mechanisms of quercetin conjugation in the intestine are not fully clarified. We examined the regioselective quercetin conjugate formation in the intestine after oral administration of quercetin glycosides, by simultaneous sampling of blood from the portal vein and superior vena cava, and quantifying various positional isomers of quercetin glucuronides and sulfates in conscious rats. Concentrations of quercetin glucuronides were higher in blood from the portal vein than the superior vena cava, showing that glucuronidation mainly occurred in the intestine. Such differences were not observed for quercetin sulfates. Regioselectivity of the intestinal glucuronidation in quercetin hydroxyl groups were 7- >3'- >3- >4'-OH. Quercetin was mainly sulfated on 3'-OH at 30 min, but on 4'-OH at 240 min.

Self-assembled amphiphilic chitosan nanoparticles for quercetin delivery to breast cancer cells.

Novel drug delivery strategies are needed to meet the complex challenges associated to cancer therapy. Biocompatible pH-sensitive drug delivery nanocarriers based on amphiphilic co-polymers seem to be promising for cancer treatment. In the present study, a drug delivery system was produced by encapsulating quercetin into novel pH-sensitive self-assembled amphiphilic chitosan nanoparticles. Up to 83% of quercetin was entrapped by the nanoparticles. The particle diameter, as measured by dynamic light scattering (DLS), ranged from ∼235 to ∼312 nm for the blank and ∼490 to ∼502 nm for the loaded carriers. The results showed that the payload release is larger at acidic pH (5.0) than at physiological pH (7.4). Fitting the data to the Korsmeyer-Peppas model indicated that anomalous diffusion is the predominant release mechanism at pH 5.0, while Fickian diffusion operates at pH 7.4. The MTT assay revealed that blank nanoparticles were non-antiproliferative for the cell tested. The results further revealed that quercetin maintains its metabolism inhibition against MCF-7 cells after encapsulation. Cellular uptake experiments showed that nanoparticles accumulated on the cell surface, whereas few were internalized. Haemocompatibility test results suggest that the nanoparticles exhibit suitable blood compatibility for biological applications. Results suggest that nanoparticles might be a promising pH-sensitive drug delivery system for applications in anticancer treatment.