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To improve the stability and solubility of Cornus officinalis flavonoid (COF), spray drying (SD), freeze-drying (FD), and microwave freeze drying (MFD) were used to encapsulate COF using whey isolate protein (WPI) and gum arabic as wall materials. The characterization of COF microparticles was performed with encapsulation efficiency (EE), particle size, morphology, antioxidant activity, structure, thermal stability, color, stability during storage, and in vitro solubility. The results showed that COF was successfully encapsulated in the wall material with an EE between 78.86% and 91.11%. The freeze-dried microparticles had the highest EE (91.11%) and the lowest particle size (12.42 ± 16.73 µm). However, the particle size of COF microparticles of SD and MFD was relatively large. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging capacity of the microparticles obtained from SD (89.36 mg V c /g) was higher than that of MFD (85.67 mg V c /g), but the drying time and energy consumption of microparticles dried by SD and MFD were lower than those of FD. Furthermore, the spray-dried COF microparticles had higher stability compared to FD and MFD when stored at 4°C for 30 days. In addition, the dissolution of COF microparticles prepared by SD and MFD was 55.64% and 57.35%, respectively, in simulated intestinal fluids, which was lower than that of FD (64.47%). Therefore, the application of microencapsulation technology showed significant advantages in improving the stability and solubility of COF, and the SD can be used for the preparation of microparticles considering energy cost and quality. PRACTICAL APPLICATION: COF is an important bioactive ingredient, but its poor stability and water solubility decreases its pharmacological value. COF microparticles can improve the stability of COF, enhance the slow-release effect, and expand its application in the food field. The drying method will affect the properties of COF microparticles. Thus, the structures and properties analysis of COF microparticles by different drying methods can provide a reference basis for the preparation and application of COF microparticles., (© 2023 Institute of Food Technologists.)

This study aims to evaluate the interaction of flavonoid-flavonoid by inhibiting the function of P-glycoprotein (P-gp). The cellular uptake of seven substrates and eleven co-incubated inhibitors was measured in KB/MDR cells. The effect of galangin or morin on the absorption of silibinin or wogonin was carried out in the rat everted gut sacs. Docking was performed to evaluate the interactions between inhibitors and P-gp. Most substrates were greatly enhanced by at least five co-incubated inhibitors. Conversely, the increased uptake of substrates coincided with a decrease or without affecting the uptake of inhibitors, implying a competitive/non-competitive inhibition on P-gp. The enhancement effect by galangin or morin on the transport of silibinin or wogonin was verified in everted gut sacs. Docking explained the inhibition of flavonoids on P-gp by competitively binding to the ATP site. These results provide a strategy for increasing the absorption of flavonoids by co-administration.

This study was aimed to investigate the inhibitory activity of flavonoids on P-glycoprotein (P-gp). Effects of 39 flavonoids on the cellular uptake (CU) of rhodamine123 (Rho) and daunomycin (DNR) were investigated in both parental KB and P-gp overexpressed KB/MDR cells. The inhibition mechanism of selected flavonoids was further investigated by measuring the ATPase activity and expression level of P-gp. Twelve flavonoids improved the uptake of Rho (↑Rho F ) and nineteen flavonoids increased the uptake of DNR (↑DNR F ) in KB/MDR cells with nine flavonoids overlapped. Structure-activity relationship (SAR) indicated that 8-OCH 3 , and 2'-OH have a negative effect on Rho and DNR transport. Whereas 5-OH, 5-OCH 3 , 6-OH, 7-OCH 3 , 3'-OH, and 4'-OH, are essential for inhibition of flavonoids on P-gp and reversing the resistance of Rho and DNR. Eleven selected flavonoids significantly induced the basal P-gp-ATPase activity but much lower than that induced by verapamil. Tangeretin, galangin, kaempferol, quercetin, and morin significantly reversed the ATPase activity stimulated by verapamil. Six of eleven flavonoids significantly decreased P-gp expression, whereas three flavonoids slightly increased P-gp expression. These results provide valuable information that flavonoids can effectively reverse multidrug resistance of P-gp-mediated transport of nutraceutical and drugs by co-administration., (Copyright © 2021. Published by Elsevier Ltd.)

This study was aimed to determine the relationship of flavonoid structures to their affinity for an important efflux transporter, multidrug-resistant associated protein 2 (MRP2). The cellular uptake (CU) of 35 flavonoids was investigated in MRP2 overexpression MDCK/MRP2 cells. Resulting data identified 8 flavonoids as MRP2 substrates based on their high CU MK with MK-571 in MDCK/MRP2 cells. Also, three substrates showed better CU MD in MDCK cells than did CU MRP in MDCK/MRP2 cells. Docking analyses showed a good correlation (R = 0.926, p = 0.003) between efflux-fold of flavonoid substrates and their docking S_scoring with the MRP2 model, indicating consistency between in silico and in vitro approaches. A structure affinity relationship (SAR) study indicated that 3-OH, 5-OH, 6-OH, 3'-OH, and 4'-OCH 3 substituents were favourable while, 8-OCH 3 , 2'-OH, 3'-OCH 3 , 4'-OH and 5'-OH were unfavourable for flavonoid affinity to MRP2. Our study provides valuable information for dietary application of flavonoids with specific structures for high absorption., (Copyright © 2019. Published by Elsevier Ltd.)

P-glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance (MDR) in cancer cells. In order to enhance the uptake of chemotherapy drugs, larger amounts of P-gp inhibitors are required. Besides several chemically synthesized P-gp inhibitors, flavonoids as P-gp inhibitors are being investigated, with their advantages including abundance in our daily diet and a low toxicity. The cytotoxicity of daunorubicin (as a substrate of P-gp) to KB/MDR1 cells and the parental KB cells was measured in the presence or absence of flavonoids. A two-dimensional quantitative structure-activity relationship (2D-QSAR) model was built with a high cross-validation coefficient (Q 2 ) value of 0.829. Descriptors including vsurf_DW23, E_sol, Dipole and vsurf_G were determined to be related to the inhibitory activity of flavonoids. The lack of 2,3-double bond, 3'-OH, 4'-OH and the increased number of methoxylated substitutions were shown to be beneficial for the inhibition of P-gp. These results are important for the screening of flavonoids for inhibitory activity on P-gp.

This study was aimed to determine the mechanism for flavonoid poor absorption related to P-glycoprotein (P-gp). The cellular uptake (CU) of 40 flavonoids was investigated in P-gp overexpressing KB/multidrug-resistant (MDR) cells. A total of 9 flavonoids, including 5,7,3',4'-tetramethoxyflavone, with a significant ( p < 0.05) CU KBE (2.90 ± 0.146 μmol/g) higher than CU KBP (1.57 ± 0.129 μmol/g) were identified as P-gp substrates. Besides, 8 substrates, including tangeretin, showed a significant ( p < 0.05) CU KB (9.72 ± 1.09 μmol/g) higher than its CU KBP (7.36 ± 0.692 μmol/g). A total of 7 of 17 flavonoid substrates stimulated the P-gp efflux of rhodamine 123, and most substrates increased P-gp expression in KB/MDR cells. Docking analyses showed a good correlation ( R = 0.764; p < 0.01) between efflux fold and S&#95;scoring of flavonoids to the P-gp model, indicating consistency between in silico and in vitro results. A structure-affinity relationship exhibited that 3-OH, 5-OH, 3'-OCH 3 , and 4'-OCH 3 are crucial for flavonoids binding to P-gp. These results provide valuable information for finding a solution to improve the absorption of flavonoids.

Flavonoids exhibit a broad range of biological activities. However, poor absorption of some flavonoids is a major limitation for use of flavonoids as nutraceuticals. To investigate the structure requirements for flavonoids intestinal absorption, transepithelial transport and cellular accumulation (CA) of 30 flavonoids were determined using the Caco-2 cell monolayer. The bilateral permeation of five types of flavonoids followed the order: flavanones ≥ isoflavones > flavones ≥ chalcones > flavonols. The concentration of flavonoids accumulated in cells did not correlate with cell penetration since the correlation coefficient between the apparent permeability coefficient ( P app ² < 0.3). Most flavonoids exhibited a ratio of 0.8-1.5 for R ² < 0.3). Most flavonoids exhibited a ratio of 0.8-1.5 for P , suggesting passive diffusion pathways. However, luteolin, morin and taxifolin may involve the efflux mechanisms. The quantitative structure-permeability relationship (QSPR) study demonstrated that the intestinal absorption of flavonoids can be related to atomic charges on carbon 3' ( app A to B / P app B to A , suggesting passive diffusion pathways. However, luteolin, morin and taxifolin may involve the efflux mechanisms. The quantitative structure-permeability relationship (QSPR) study demonstrated that the intestinal absorption of flavonoids can be related to atomic charges on carbon 3' ( Q 1) and solvation energy of flavonoids ( C3' ). These results provide useful information for initially screening of flavonoids with high intestinal absorption.S log P&#95;V 3), balance between the center of mass and position of hydrophobic region ( vsurf&#95;ID 1) and solvation energy of flavonoids ( E&#95;sol ). These results provide useful information for initially screening of flavonoids with high intestinal absorption., Competing Interests: The authors declare no conflict of interest.

Isoflavones are one group of the major flavonoids and possess multiple biological activities due to their antioxidant properties. However, a clear antioxidant mechanism of dietary isoflavones is still remained to be answered. In this study, the effects of isoflavones on the nuclear factor E2‐related factor 2 (Nrf2)–antioxidant response element (ARE) signaling pathway and the underlying molecular mechanisms were investigated. Results showed that isoflavones are potential Nrf2–ARE activators while their activities were structure dependent. Biochanin A (BCA), an O‐methylated isoflavone with low direct antioxidant activity, can effectively protect HepG2 cells against tert‐butyl hydroperoxide (t‐BHP)‐induced oxidative damage via activation of the Nrf2 signaling, and thereby the induction of downstream cytoprotective enzymes including NAD(P)H quinone oxidoreductase‐1, heme oxygenasae‐1, and glutamate‐cysteine ligase catalytic subunit. A molecular docking study revealed that BCA could directly bind into the pocket of Kelch‐like erythroid cell‐derived protein with CNC homology (ECH)‐associated protein 1 (Keap1), a cytoplasmic suppressor of Nrf2, to facilitate Nrf2 activation. The upstream mitogen‐activated protein kinase (MAPK) pathways were also involved in the activation of Nrf2 signaling. These findings indicate that the protective actions of dietary isoflavones against oxidative damage may be at least partly due to their ability to enhance the intracellular antioxidant response system by modulating the Nrf2−ARE signaling pathway. [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance (MDR) in cancer cells. In order to enhance the uptake of chemotherapy drugs, larger amounts of P-gp inhibitors are required. Besides several chemically synthesized P-gp inhibitors, flavonoids as P-gp inhibitors are being investigated, with their advantages including abundance in our daily diet and a low toxicity. The cytotoxicity of daunorubicin (as a substrate of P-gp) to KB/MDR1 cells and the parental KB cells was measured in the presence or absence of flavonoids. A two-dimensional quantitative structure–activity relationship (2D-QSAR) model was built with a high cross-validation coefficient (Q2) value of 0.829. Descriptors including vsurf_DW23, E_sol, Dipole and vsurf_G were determined to be related to the inhibitory activity of flavonoids. The lack of 2,3-double bond, 3′-OH, 4′-OH and the increased number of methoxylated substitutions were shown to be beneficial for the inhibition of P-gp. These results are important for the screening of flavonoids for inhibitory activity on P-gp. [ABSTRACT FROM AUTHOR]

This study characterized the nanoparticles and the binding mechanism between pH-shifted soy β-conglycinin (β-CG) and hesperetin (Ht)/hesperidin (Hd). Different structural characteristics and concentrations of Ht/Hd were found to affect the encapsulation efficiency, loading amount, and particle size of pH-shifted β-CG‒Ht/Hd nanoparticles. This was the result of two glycosyl substituents (7-position of the C-ring) in the presence of Hd containing six hydroxyl groups interacting with the polar groups of proteins to form hydrogen bonds, which facilitated the formation of nanocomplexes. Besides, the exposed hydrophobic groups in the β-CG proteins resulting from pH shift treatment developed hydrophobic interactions with the benzene ring or glucoside in the flavonoids. Moreover, Ht/Hd strongly quenched the fluorescence of pH-shifted β-CG in static mode. After binding with flavonoids, the tertiary and secondary structures of pH-shifted β-CG were significantly changed. The finding presented in this study provided evidence of the binding mechanism of soy proteins and different structural flavonoids and will aid in the design of soy protein/flavonoid enriched-food. • Binding mechanisms of Ht/Hd to pH-shifted β-CG were investigated. • Different structures and concentrations of Ht and Hd affected the binding. • Ht/Hd quenched the intrinsic fluorescence of pH-shifted β-CG in a static mode. • Hydrophobic interactions and hydrogen bonds mainly drove the binding. • The binding affected the tertiary and secondary structures of pH-shifted β-CG. [ABSTRACT FROM AUTHOR]

Apigenin is a vital flavonoid that has attracted considerable attention in recent years due to its potent health benefits. Pumpkin seed protein (PSP) is a valuable by-product after pumpkin seed processing. However, the non-covalent interaction mechanism between apigenin and PSP remains to be explored. Here, the structural and conformational changes and molecular mechanisms underlying their interaction were investigated using multi-spectroscopic analysis integrated with molecular simulation approaches. The experimental results indicated that apigenin statically quenched the intrinsic fluorescence of PSP, indicating that the interaction between them did occur. Thermodynamic analysis and computational simulation results showed that the driving forces between apigenin and PSP were the hydrophobic interactions that predominated. The binding of apigenin resulted in changes in the conformation, microenvironment, and surface hydrophobicity of PSP. Furthermore, it was revealed by molecular docking and molecular dynamic (MD) simulations that apigenin maintained binding stability in the hydrophobic pockets of the protein through its interaction with several key residues. Additionally, it was found that the movement strength and directions of individual resides were altered after apigenin binding, which is the molecular basis of protein structural and conformational changes induced by apigenin. This study may provide theoretical evidence for the potential application of PSP and apigenin complex products in the food industry. [Display omitted] • The non-covalent binding for pumpkin seed protein (PSP) and apigenin was explored. • The fluorescence quenching of PSP by apigenin was mainly static quenching. • The binding of apigenin changed the conformation of PSP. • The dominant driving forces for PSP and apigenin were hydrophobic interactions. • Apigenin could keep stable in the binding pocket during molecular dynamic simulation. [ABSTRACT FROM AUTHOR]