Binding Of Quercetin Research Articles

Evidence for the Quercetin Binding Site of Glycogen Phosphorylase as a Target for Liver-Isoform-Selective Inhibitors against Glioblastoma: Investigation of Flavanols Epigallocatechin Gallate and Epigallocatechin.

Glycogen phosphorylase (GP) is the rate-determining enzyme in glycogenolysis, and its druggability has been extensively studied over the years for the development of therapeutics against type 2 diabetes (T2D) and, more recently, cancer. However, the conservation of binding sites between the liver and muscle isoforms makes the inhibitor selectivity challenging. Using a combination of kinetic, crystallographic, modeling, and cellular studies, we have probed the binding of dietary flavonoids epigallocatechin gallate (EGCG) and epigallocatechin (EGC) to GP isoforms. The structures of rmGPb-EGCG and rmGPb-EGC complexes were determined by X-ray crystallography, showing binding at the quercetin binding site (QBS) in agreement with kinetic studies that revealed both compounds as noncompetitive inhibitors of GP, with EGCG also causing a significant reduction in cell viability and migration of U87-MG glioblastoma cells. Interestingly, EGCG exhibits different binding modes to GP isoforms, revealing QBS as a promising site for GP targeting, offering new opportunities for the design of liver-selective GP inhibitors.

Integrated network pharmacology, metabolomics and molecular docking analysis to reveal the mechanisms of quercetin in the treatment of hyperlipidemia

Hyperlipidemia (HLP) is a significant contributor to cardiovascular diseases. Quercetin (QUE), a naturally occurring flavonoid with diverse bioactivities, has garnered attention due to its potential therapeutic effects. However, the precise mechanisms underlying the effects of QUE on HLP remain unclear. In this study, an ultra-high-performance liquid chromatography-quadrupole/electrostatic field Orbitrap high-resolution mass spectrometry (UPLC-Q-Exactive-MS) metabolomics strategy was employed to obtain metabolite profiles, and potential biomarkers were identified following data analysis. Network pharmacology and Drug Affinity Responsive Target Stability (DARTS) assays were utilized to explore the potential targets of QUE for HLP treatment. The results of metabolomics and network pharmacology were then integrated to identify the key targets and metabolic pathways involved in the therapeutic action of the QUE against HLP. Molecular docking and experimental validation were performed to confirm these key targets. A comprehensive database search identified 138 QUE-HLP-related targets. A protein-protein interaction (PPI) network was constructed using STRING, and the shared targets were filtered with Cytoscape. Among these, AKT1, TNF, VEGFA, mTOR, SREBP1, and SCD emerged as potential therapeutic targets. These findings were validated using in vitro cell experiments. Additionally, the mechanism of action of QUE against HLP was evaluated by integrating network pharmacology with metabolomics, identifying two metabolomic pathways crucial to HLP treatment. DARTS experiments confirmed the stable binding of QUE to FASN, p-mTOR, SREBP1, and p-AKT. In HepG2 cells treated with palmitic acid (PA), QUE significantly reduced the mRNA expression of ACLY, ACACA, FASN, and SCD (p < 0.05). Western blot analysis revealed that PA significantly increased protein expression of p-mTOR, SREBP1, FASN, and p-AKT (p < 0.05). In summary, our study provides novel insights into the protective mechanisms of QUE against HLP and offers valuable information regarding its potential benefits in clinical treatment.

Electrostatically self-assembled magnetized MXene/copper ferrite nanospheres hybrids: Evaluation of molecularly imprinted electrochemical sensor for the quercetin antioxidant supplement

Quercetin, a bioflavonoid with significant biological activities, is beneficial for health. Herein, a pioneering molecularly imprinted electrochemical sensor utilizing an MXene/CuFe2O4 magnetic nanosphere hybrid was developed for the first time to detect quercetin ultra-sensitively. CuFe2O4 nanospheres (average 189 nm) were synthesized and combined with MXene sheets, then electrostatically deposited onto a magnetic carbon paste electrode. A functional monomer was then electropolymerized onto this hybrid-modified electrode to form an imprinted polymeric layer, tailored for quercetin binding. Characterizations confirmed the morphological and magnetic properties of the materials. The sensor’s response factors were optimized, achieving a low detection limit of 1.6 nM and two linear ranges (0.005–0.7 μM and 0.7–10 μM). The sensor showed excellent stability, repeatability, reproducibility, and selectivity, and was successfully used to quantify quercetin in dietary supplements.

New molecular mechanisms of quercetin in improving recurrent spontaneous abortion based on in-depth network pharmacology and molecular docking.

The increasing prevalence of recurrent spontaneous abortion (RSA) poses significant physical and psychological challenges for affected individuals. Quercetin, a natural plant flavonoid, shows promise in reducing miscarriage rates, yet its precise mechanism remains elusive. This study uses network pharmacology, molecular docking, and experimental validation to explore the molecular pathways through which quercetin mitigates RSA. Quercetin-related target genes were sourced from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and RSA target genes were retrieved from the Comparative Toxicogenomics Database (CTD), with overlapping targets identified using Venn diagrams. All genes were visualized using the STRING database, and core targets were selected with Cytoscape 3.7.3. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using the DAVID and Reactome online resources. Subsequently, HTR-8/SVneo cells were stimulated with lipopolysaccharide (LPS) and treated with varying concentrations of quercetin (1, 5, and 10μM), then subjected to CCK-8, wound healing, transwell, and annexin V-FITC/PI apoptosis assays. Reverse-transcription quantitative PCR was used to determine the mRNA expression levels of IL-1β, TNF-α, and IL-6 in LPS-induced cells post-quercetin intervention, and western blotting was used to measure AKT1, MMP9, and caspase-3 protein levels. A total of 139 quercetin-associated target genes were identified from the TCMSP database, and 98 disease-associated target genes were obtained from the CTD, resulting in 25 shared target genes. Gene ontology enrichment highlighted the involvement of these targets in positive regulation of apoptosis, response to hypoxia, and intrinsic apoptotic signaling pathway in response to DNA damage. KEGG pathway analysis indicated enrichment in pathways related to interleukin-4 and interleukin-13 signaling, cytokine signaling in the immune system, and apoptosis. Molecular docking studies revealed robust binding of quercetin with MMP9, AKT1, IL-1β, TNF, and caspase-3. In vitro experiments demonstrated that quercetin enhanced LPS-induced cell activity, fostering proliferation, migration, and invasion, and reducing apoptosis. Moreover, quercetin reduced IL-1β, TNF-α, and IL-6 mRNA expression, increased AKT1 and MMP9 protein levels, and reduced caspase-3 expression. Quercetin could mitigate the incidence of RSA by modulating inflammatory responses and apoptotic processes, through upregulation of AKT1 and MMP9, and downregulation of caspase-3, IL-1β, TNF-α, and IL-6. Quercetin opens up a new way of thinking about treating RSA.

Studies on in vivo antithrombotic activity of quercetin, a natural flavonoid isolated from a traditional medicinal plant, African eggplant (Solanum indicum)

Ethnopharmacological relevanceEvery year, cardiovascular diseases (CVDs) account for about 17.9 million deaths, making them the primary cause of both morbidity and mortality. Conventional drugs, which are often prescribed to treat cardiovascular diseases, are costly and have adverse effects. Consequently, dietary modifications and other medications are needed. Traditional use of Solanum indicum as cardiotonic to treat hypertension and anticoagulant potency has been reported but poorly evaluated scientifically. Aim of the studyThis study investigated the in vivo anticoagulant activity and mechanism of anticoagulation of quercetin (QC), a bioactive compound isolated from S. indicum (SI) hydroethanolic fruit extract. Materials and methodsBioassay-guided fractionation (anticoagulant activity) extracted QC from hydroethanolic SI extract. QC was extensively characterized biochemically and pharmacologically. The interaction between QC and thrombin was investigated using spectrofluorometric and isothermal calorimetric methods. Cytotoxicity, antiplatelet, and thrombolytic studies were carried out in vitro. The Swiss albino mice were used to assess the in vivo, anticoagulant, and antithrombotic activities of QC. ResultsQC exhibits anticoagulant activity via (i) uncompetitive inhibition of thrombin but not FXa with a Ki value of 33.11 ± 4.2 μM and (ii) a partial inhibition of thrombin-catalyzed platelet aggregation with an IC50 value of 13.2 ± 1.2 μM. The experimental validation of the in silico study's prediction of QC's binding to thrombin was confirmed by spectrofluorometric and isothermal calorimetric analyses. QC was nontoxic to mammalian, non-hemolytic cells and demonstrated thrombolytic activity by activating plasminogen. QC demonstrated in vivo anticoagulant efficacy, preventing k-carrageen-induced thrombus formation in mice's tails. In the acute circulatory stasis paradigm in mice, QC reduces thromboxane B2 (TXB2) and endothelin-1 (ET-1) while increasing nitric oxide synthase (eNOS) and 6-keto prostaglandin F1α (6-keto-PGF1 α). ConclusionEffective in vivo anticoagulant and antithrombotic properties of S. indicum's bioactive component QC point to the plant's potential use as a herbal anticoagulant medication for preventing and treating cardiovascular diseases linked to thrombosis.

Anti-diabetic, anti-pancreatic lipase, and anti-protein glycation potential of Irvingia gabonensis stem bark extracts: in vitro and in silico studies.

Diabetes mellitus is a chronic metabolic disorder that affects glucose, lipid, and protein metabolism. Targeting these metabolic derangements can optimize the therapeutic strategies for this disease. Utilizing in vitro and in silico models, this study investigated the ability of aqueous and ethanol extracts of Irvingia gabonensis to inhibit α-amylase, α-glucosidase, pancreatic lipase, and protein glycation. High-performance liquid chromatography (HPLC) was used to identify the compounds found in the stem bark of I. gabonensis. In silico analysis determined the binding mode and mechanism of interactions between the enzymes and phytochemicals. With an IC50 value of 11.47µg/ml, the aqueous extract demonstrated higher inhibitory efficacy against α-amylase compared to the ethanol extract (IC50 19.88µg/ml). However, the ethanol extract had stronger inhibitory activities against α-glucosidase, pancreatic lipase, and protein glycation compared to the aqueous extract (IC50 values of 3.05, 32.85, 0.0014 versus 25.72, 332.42, 0.018µg/ml respectively). Quercetin ranked highest in binding energy with α-amylase (-6.6kcal/mol), α-glucosidase (-6.6kcal/mol), and pancreatic lipase (-5.6kcal/mol). This was followed by rhamnetin (6.5, 6.5, and 6.1kcal/mol respectively). Hydrogen bonding, hydrophobic interactions, and pi-pi stacking are forces responsible for the binding of quercetin and rhamnetin to these enzymes. Molecular dynamics simulation showed that the lead phytochemicals formed stable and energetically stabilized complexes with the target proteins. This study showed that the extracts of I. gabonensis stem bark had significant in vitro anti-diabetic, anti-pancreatic lipase, and anti-protein glycation activities. The strong binding affinities of some of the identified compounds could be responsible for the inhibitory potential of the extracts. I. gabonensis stem bark could be further explored as a natural remedy for the treatment of diabetes mellitus and its complications.

Effect of quercetin on the protein-substrate interactions in SIRT6: Insight from MD simulations

SIRT6 is of interest for its promising effect in the treatment of aging-related diseases. Studies have shown quercetin (QUE) and its derivatives have varying degrees of effect on the catalytic effect of SIRT6. In the research, the effect of QUE on the protein-substrate interaction in the SIRT6-mediated mono-ADP ribosylation system was investigated by conventional molecular dynamics (MD) simulations combined with MM/PBSA binding free energy calculations. The results show that QUE can bind stably to SIRT6 with the binding energy of −22.8 kcal/mol and further affect the atomic interaction between SIRT6 and NAD+ (or H3K9), resulting in an increased affinity between SIRT6-NAD+ and decreased SIRT6-H3K9 binding capacity. At the same time, the binding of QUE can also alter some structural characteristics of the protein, with large shifts occurring in the residue regions involving the N-terminal (residues 1–27), Rossmann fold regions (residues 55–92), and ZBD (residues 164–179). Thus, QUE shows great potential as a scaffold for the design of novel potent SIRT6 modulators.

Simultaneous binding of quercetin and catechin to FOXO3 enhances IKKα transcription inhibition and suppression of oxidative stress-induced acute alcoholic liver injury in rats

IntroductionOxidative stress is one of the major contributors to acute alcoholic liver injury (AALI), which is a common alcoholic liver disease. Quercetin and catechin are flavonoid antioxidants present in plant foods and possess chemopreventive and chemotherapeutic activities. Quercetin and catechin are often included in the same meal and ingested together. While they show cooperative actions against oxidative damage, the underlying mechanisms behind their counteracting effects against oxidative stress-induced AALI remain poorly understood. ObjectivesThe aim of this study was to understand the mechanism underlying the enhanced antioxidant effect of quercetin-catechin combination to alleviate AALI in rats. MethodsThe ethanol (EtOH)-treated rats and H2O2-treated liver cells were used to demonstrate the enhanced antioxidant effect of quercetin and catechin. Then we used RNA-sequencing to compare quercetin alone, catechin alone and quercetin-catechin combination and then identified the critical role of IKKα combining with gene silencing and overexpression techniques. Its transcription factor, FOXO3 was found through yeast one-hybrid assay, luciferase reporter assay, EMSA and ChIP assay. Finally, the interaction between quercetin, catechin and FOXO3 was verified through molecular docking, UV–Vis absorption spectroscopy, fluorescence spectroscopy, and CD spectroscopy. ResultsThe study demonstrated the enhanced antioxidant effect of a quercetin-catechin combination in EtOH-treated rats and in H2O2-treated liver cells. Quercetin and catechin cooperatively inhibited IKKα/p53 pathway and activated Nrf2 signaling pathway. IKKα was a critical negative regulator in their joint action. FOXO3 bound to IKKα promoter to regulate IKKα transcription. Quercetin and catechin influenced FOXO3-IKKα binding through attaching directly to FOXO3 at different sites and altering FOXO3′s secondary structures. ConclusionOur study revealed the mechanism of quercetin and catechin against oxidative stress-induced AALI through jointly interacting with transcription factor. This research opens new vistas for examining the joint effect of therapeutics towards functional proteins and confirms the chemopreventive effects of multiple flavonoids via co-regulation.

Structural, material and antibacterial properties of quercetin incorporated soy protein isolate films and its binding behavior through molecular docking.

This study aimed to investigate the three different methods for the fabrication of quercetin (1%-3% w/w of protein) incorporated soy protein isolate (SPI) films and their effect on material properties. The quercetin incorporated SPI films prepared by these methods were characterized by Fourier transform infrared (FTIR) spectroscopy, UV-Vis spectrophotometer, tensile properties, and water uptake and leaching properties. The cross-linking pattern was revealed by the FTIR spectrum that showed formation of an ester group because of interaction between the quercetin hydroxyl group and the carboxyl side chain of SPI amino acids. The tensile strength of SPI films were enhanced with the addition of quercetin as it increased to a maximum of 6.17 MPa while neat SPI film had tensile strength 4.13 MPa. The prepared films exhibit significant antibacterial activity against Listeria monocytogenes and Escherichia coli. The In-silico docking analysis demonstrates that covalent and non-covalent forces play crucial roles in binding interaction. It shows the formation of four hydrogen bonds, two salt bridges along with one pi-alkyl interaction. The simulation studies reflect the crucial amino acid residues involved in SPI-quercetin binding. The effect of quercetin binding with SPI on its stability and compactness is revealed by Root mean square deviation (RMSD) and radius of gyration studies.

Novel designed analogues of quercetin against SARS-CoV2:an in-silico pharmacokinetic evaluation, molecular modeling, MD simulations based study

Here we present the design of the series of quercetin analogues and their molecular docking study involving the binding of quercetin and its analogues with SARS-CoV2 3CLpro. The scientific literature shows that quercetin compound has been successfully used against SARS-CoV by inhibiting the replication of virus in respiratory epithelial cell through the inhibition of the SARS-CoV main protease (3CLpro.) It was suggested that the modification at position 3 in quercetin structure may produce potent compounds against SARS-CoV2. A series of quercetin analogues were designed and screened for physicochemical and pharmacokinetics parameters. The activities of selected compounds against SARS-CoV2 were screened by molecular modelling and evaluated that analogues, Q5, Q6 and Q13 have the best docking scores (-8.01 to −8.17 kcal/mol) and also better than quercetin, α-ketoamide and current available inhibitors of the same target. The structure-activity relationship (SAR) study revealed that the introduction of the amino group in a designed molecule was highly promising for increasing the inhibitory activity against SARS-CoV2 3CL pro. Moreover, to check the stability and orientation of selected compounds inside the binding pocket, the molecular dynamic simulations were performed for 100 ns. Results revealed that the designed analogues Q1, Q6 and Q13 having lowest binding energies (-8.0, −8.17 and −8.06 kcal/mol respectively) as well as better physicochemical properties, pharmacokinetics, and toxicity profile show their potential to synthesize and develop as the therapeutic agents against corona virus. Communicated by Ramaswamy H. Sarma

Effect of Cucurbit[7]uril on contrasting binding with flavonoids: Insights from spectroscopy and calorimetric studies

AbstractDue to intrinsic fluorescence behavior, and the environment‐dependent excited‐state intramolecular proton transfer (ESIPT) process, makes special attention towards flavonoids for conducting photophysical study. The binding of fisetin, morin hydrate, and quercetin with macrocyclic molecule Cucurbit[7]urils (CB[7]) has been studied using different spectroscopic methods. The changes in the thermodynamic parameters during complex formation between the flavonoids with CB[7] are estimated by an isothermal titration calorimetry study. From the spectroscopic measurement, we have seen that in the presence of CB[7], flavonoids show the ESIPT process and the prototropic equilibrium is present between different forms of flavonoids. The isothermal titration calorimetry study shows that the complex formation between these flavonoids with CB[7] spontaneously takes place at room temperature, which is an endothermic process.

A novel multi-hyphenated approach to screen and character the xanthine oxidase inhibitors from saffron floral bio-residues

Recently, the incidence of hyperuricemia increased with patient rejuvenation, searching for new xanthine oxidase (XOD) inhibitors from natural products becomes important. In our previous work, a flavonoid extract of saffron floral bio-residues (SFB) was found to alleviate hyperuricemia via inhibiting XOD. In this study, an integrated approach combining two-dimensional liquid chromatography, surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) was developed to online screen and character the potential XOD inhibitors from SFB. The two-dimensional liquid chromatography consisted of affinity chromatography and reverse phase chromatography (2D-AR), in which an XOD column, an inactive XOD column, and a control column were used in the first dimensional liquid chromatography to avoid phenomena of “false positive” and “missing screen of compounds with weak affinity to XOD” that often occur in the screening process, and a C18 column was used in the second dimensional liquid chromatography to separate the mixed XOD binders. Four flavonoid glycosides, i.e., quercetin-3-O-sophoroside (QS), kaempferol-3-O-sophoroside (KS), kaempferol-3-O-rutinoside (KR), and kaempferol-3-O-glucoside (KG), were thus successfully screened and identified from SFB extract by the 2D-AR method. The affinity of QS, KS, KR, KG, kaempferol (aglycone of KS, KR and KG), and quercetin (aglycone of QS) binding to XOD was investigated using SPR method, with KD ranged from 4.8 μM to 47.6 μM. The inhibitor constant (KI) of KS, KR, KG, quercetin and kaempferol were 4.92 mM, 1.11 mM, 0.294 mM, 4.93 μM and 3.27 μM, respectively, determined using ITC method. Finally, the anti-XOD activities of KS, the most abundant flavonoid in SFB extract, and kaempferol in hyperuricemia mice were verified, which suggested that the multi-hyphenated approach established herein can be applied for screen and character the XOD inhibitors in natural products.

Towards understanding the interaction of quercetin with chitosan-phytate complex: An experimental and computational investigation

Spectroscopic and structural properties of quercetin (QE) encapsulated in chitosan-phytate anion (CT-PA) nanoparticles were investigated, and an all-atom model was employed for molecular dynamics simulations to broaden the perspective on the conformational and energetics aspects regarding the quercetin-chitosan complexation. Quercetin binding to the free chitosan chains and its encapsulation in the nanoparticle obtained in the presence of the phytate anion was confirmed using dynamic light scattering and Fourier-transform infrared spectroscopy, and a considerably hindered rotational motion of the probe bound to the chitosan strand was demonstrated by the steady-state and anisotropy fluorescence measurements. While morphologies ranging from nearly spherical nanoparticles to nanofibrils were observed through atomic force microscopy upon increasing the chitosan content, a high encapsulation efficiency of QE, weakly dependent on the size and shape of CT-PA nanoparticles, was found. Simulation-based structural and energetics predictions indicated a similar H bond pattern for the QE binding to the chitosan strands, either in a free state or reticulated with the aid of the phytic anion. Additional crosslinker-assisted retention of quercetin in the chitosan network, as well as an enhanced electrostatic contribution to the binding free energy obtained at encapsulation, were derived from molecular dynamics simulations.

Biomimetic retractable DNA nanocarrier with sensitive responsivity for efficient drug delivery and enhanced photothermal therapy

BackgroundThe coalition of DNA nanotechnology with diversiform inorganic nanoparticles offers powerful tools for the design and construction of stimuli-responsive drug delivery systems with spatiotemporal controllability, but it remains challenging to achieve high-density oligonucleotides modification close to inorganic nanocores for their sensitive responsivity to optical or thermal signals.ResultsInspired by Actinia with retractable tentacles, here we design an artificial nano-Actinia consisted of collapsible DNA architectures attached on gold nanoparticle (AuNP) for efficient drug delivery and enhanced photothermal therapy. The collapsible spheroidal architectures are formed by the hybridization of long DNA strand produced in situ through rolling circle amplification with bundling DNA strands, and contain numerous double-helical segments for the intercalative binding of quercetin as the anti-cancer drug. Under 800-nm light irradiation, the photothermal conversion of AuNPs induces intensive localized heating, which unwinds the double helixes and leads to the disassembly of DNA nanospheres on the surface of AuNPs. The consequently released quercetin can inhibit the expression of heat shock protein 27 and decrease the thermal resistance of tumor cells, thus enhancing photothermal therapy efficacy.ConclusionsBy combining the deformable DNA nanostructures with gold nanocores, this Actinia-mimetic nanocarrier presents a promising tool for the development of DNA-AuNPs complex and opens a new horizon for the stimuli-responsive drug delivery.Graphical

Quercetin Induces Apoptosis in HepG2 Cells via Directly Interacting with YY1 to Disrupt YY1-p53 Interaction

Quercetin is a flavonol found in edible plants and possesses a significant anticancer activity. This study explored the mechanism by which quercetin prevented liver cancer via inducing apoptosis in HepG2 cells. Quercetin induced cell proliferation and apoptosis through inhibiting YY1 and facilitating p53 expression and subsequently increasing the Bax/Bcl-2 ratio. The results revealed that YY1 knockdown promoted apoptosis, whilst YY1 overexpression suppressed apoptosis via direct physical interaction between YY1 and p53 to regulate the p53 signaling pathway. Molecular docking using native and mutant YY1 proteins showed that quercetin could interact directly with YY1, and the binding of quercetin to YY1 significantly decreased the docking energy of YY1 with p53 protein. The interactions between quercetin and YY1 protein included direct binding and non-bonded indirect interactions, as confirmed by cellular thermal shift assay, UV-Vis absorption spectroscopy, fluorescence spectroscopy and circular dichroism spectroscopy. It was likely that quercetin directly bound to YY1 protein to compete with p53 for the binding sites of YY1 to disrupt the YY1-p53 interaction, thereby promoting p53 activation. This study provides insights into the mechanism underlying quercetin's anticancer action and supports the development of quercetin as an anticancer therapeutic agent.

Investigation renin inhibitor activity from flavonoids derivates by in silico study.

Flavonoids have various pharmacological activities, such as antihypertensive, anticancer, and and antidiabetic effects. Several studies have shown that luteolin, quercetin, kaempferol, myricetin, naringenin, hesperetin, and epicatechin have antihypertensive effects, but the mechanism of action has yet to be discovered with certainty. This study aims to identify flavonoids from luteolin, quercetin, kaempferol, myricetin, naringenin, hesperetin, and epicatechin as renin inhibitors through in silico study; seven flavonoid compounds were docked with 2V0Z with renin inhibitor (Aliskiren) in humans (Homo sapiens 6 LU7) using AutoDock v4.2.6. SwissADME was used to evaluate the pharmacokinetic characteristics of these substances. Results molecular binding of luteolin, quercetin, kaempferol, myricetin, naringenin, hesperetin, and epicatechin, has potential as renin inhibitors with affinity energy values lower than those of aliskiren of -9.3; -9.3; -10.0; -9.2; -9.9; -9.3; and -9.7 kcal/mol. The interactions of these seven compounds have the same catalytic activity as aliskiren on two aspartic acid residues, Asp32 and Asp215. The analysis of pharmacokinetic profiles and the search for physical and chemical properties showed that the seven compounds violated three of the five Lipinski rules, while aliskiren violated one. Hesperitin, kaempferol, and naringenin had similarities with aliskiren on the amino-acid residues in the renin-binding pocket. However, based on pharmacokinetic analysis, the three compounds had an oral pharmacokinetic profile that could have been better than aliskiren.

Formulation and evaluation of a novel megalomeric microemulsion from tamarind seed xyloglucan-megalosaccharides for improved high-dose quercetin delivery

Megalomeric microemulsion is a new term referring to lipid-based formulation using amphiphilic megalosaccharide as a coexcipient. Quercetin is a dose-dependent bioactive compound and has promising therapeutic potential, but its low water solubility and permeability restrict its treatment efficacy. We aimed to formulate high-dose quercetin loaded into colloidal micelles by the self-micro emulsifying system (SMES) in combination with Tween 80, isopropyl myristate, and xyloglucan megalosaccharide (X-MS). X-MS is a moderate-size heterologous saccharide obtained from enzymatic cleavage of tamarind seed xyloglucan. X-MSs with an average degree of polymerization of 16 and 56 were investigated to bearing their surface hydrophobic interaction with a fluorescence probe 6-(p-toluidino)-2-naphthalene-6-sulfonate yielded the binding constant values of 127 and 180 M−1, respectively and X-MS itself displayed a slight effect on quercetin binding. However, the implementation of X-MSs toward SMES was highly compatible because X-MS molecules were confined in micellular solutions. Consequently, X-MSs improved the quercetin loading from 1 to 2 to 12.5–17.7 mg/mL based on the composition ratio, X-MS chain lengths, and X-MS concentrations (0.15–3.0%, w/v) and stabilized the quercetin-loaded oil-in-water SMES. The optical appearances were transparent yellow containing uniformly fine droplets with diameters of 11–12 nm. In vitro radical scavenging activity tests with 2,2-diphenyl-1-picrylhydrazyl showed that the megalomeric microemulsions improved the half-maximal inhibitory concentration (IC50 = 22–24 μg/mL) over that of the X-MS-free microemulsion. This study provided a new approach of liquid supplementation from commercially unavailable-size xyloglucan to be a promising added-value agent for oral uptake of quercetin.

Modification of structural and functional characteristics of casein treated with quercetin via two interaction modes: Covalent and non-covalent interactions

Preparation of complexes via interactions between proteins and polyphenols has become one of the methods to effectively improve utilization of proteins. In this study, the structural and functional characteristics modification of casein treated with different concentrations of quercetin (10, 20, 40, 80 and 160 μmol/g protein) via covalent and non-covalent interactions were investigated. Results revealed that covalent complexes had lower sulfhydryl group content and higher quercetin binding capacity than non-covalent ones at the same quercetin concentration. This was consistent with the results of fluorescence spectroscopy which revealed higher fluorescence quenching constant and binding sites number for the covalent complexes. Fourier transform infrared spectroscopy demonstrated similar secondary structural changing trend for covalent and non-covalent complexes. The α-helix, β-turn and random coil contents increased with increasing quercetin concentration while β-sheet content decreased. Addition of quercetin decreased surface hydrophobicity of the complexes, regardless of covalent or non-covalent interactions. Casein solubility was improved in covalent interaction, while the non-covalent interaction impaired it. Quercetin treatment improved foaming activity, emulsifying activity and antioxidant activity while decreasing foaming stability and emulsifying stability. The results could provide a theoretical foundation for potential applications of casein-quercetin complexes in the food industry.

Three to Tango: Inhibitory Effect of Quercetin and Apigenin on Acetylcholinesterase, Amyloid-β Aggregation and Acetylcholinesterase-Amyloid Interaction.

One of the pathological hallmarks of Alzheimer's disease (AD) is the formation of amyloid-β plaques. Since acetylcholinesterase (AChE) promotes the formation of such plaques, the inhibition of this enzyme could slow down the progression of amyloid-β aggregation, hence being complementary to the palliative treatment of cholinergic decline. Antiaggregation assays performed for apigenin and quercetin, which are polyphenolic compounds that exhibit inhibitory properties against the formation of amyloid plaques, reveal distinct inhibitory effects of these compounds on Aβ40 aggregation in the presence and absence of AChE. Furthermore, the analysis of the amyloid fibers formed in the presence of these flavonoids suggests that the Aβ40 aggregates present different quaternary structures, viz., smaller molecular assemblies are generated. In agreement with a noncompetitive inhibition of AChE, molecular modeling studies indicate that these effects may be due to the binding of apigenin and quercetin at the peripheral binding site of AChE. Since apigenin and quercetin can also reduce the generation of reactive oxygen species, the data achieved suggest that multitarget catechol-type compounds may be used for the simultaneous treatment of various biological hallmarks of AD.

Binding of Quercetin to Hemoglobin Reduced Hemin Release and Lipid Oxidation.

The interactions between quercetin and bovine (or human) hemoglobin (Hb) were systematically investigated by fluorescence, UV-vis absorption spectroscopy, and molecular docking to demonstrate the structural mechanism by which quercetin affected the Hb redox state and stability. Quercetin could interact with the central cavity of the Hb molecule with one binding site to generate an Hb-quercetin complex, and the hydrophobic interaction played an important role in the formation of the complex. The binding constant for the Hb-quercetin complex at 298 K was observed to be 1.25 × 104 M-1. In addition, quercetin effectively inhibited Hb-induced lipid oxidation in liposomes or washed muscles, which was ascribed to the conversion to oxy-Hb and decreased hemin dissociation from met-Hb. Consistent with its lower abilities to bind Hb and scavenge free radicals, rutin (i.e., quercetin-3-rhamnosylglucsoside) did not significantly influence the redox state of Hb nor reduce hemin release from Hb, and subsequently, it less effectively inhibited Hb-induced lipid oxidation than quercetin. Altogether, the results herein provide novel insights into the antioxidant mechanism for quercetin and are beneficial to the application of natural quercetin in Hb-containing foods.