Impact of refining on phytochemicals and anti-inflammatory activity of papaya (Carica papaya L.) seed oil in LPS-stimulated THP-1 cells.

This study investigated the changes in phytochemical composition and inflammatory response of crude papaya (Carica papaya L.) seed oil (CPO) and its refined forms (degummed, PDG; deacidified, PDA; decolorized, PDC; deodorized, PDO). Oils were analyzed for their phytochemical composition, oil quality parameters, antioxidant activity, and their inflammatory response in LPS-stimulated THP-1 macrophages. At higher refining degrees, particularly after deacidification, the contents of phytochemicals (sterols, tocopherols, and polyphenols) decreased while oxidation products increased. Both CPO (0.1-1.0 mg/mL) and PDG reduced the secretion and mRNA expression of LPS-stimulated inflammatory cytokines and mediators and also blocked the activation of the NF-κB pathway. PDA, PDC, and PDO showed low anti-inflammatory or even pro-inflammatory activity. Correlation analysis showed that 4 polyphenols and 2 phytosterols were responsible for the oil's anti-inflammatory effects. These findings indicated that moderate refining is suggested for papaya seed oil processing for retaining bioactive ingredients and anti-inflammatory ability.

Amelioration of Type 2 Diabetes Using Four Strains of Lactobacillus Probiotics: Effects on Gut Microbiota Reconstitution-Mediated Regulation of Glucose Homeostasis, Inflammation, and Oxidative Stress in Mice.

This study aims to explore the preventive effects and underlying mechanisms of Lactobacillus fermentum CKCC1858 (CKCC1), L. fermentum CKCC1369 (CKCC2), Lactobacillus plantarum CKCC1312 (CKCC3), and Lactobacillus gasseri CKCC1913 (CKCC4) on high-fat diet combined with streptozotocin (HFD/STZ)-stimulated type 2 diabetes (T2D) in mice. Generally, the results indicated that most of the four probiotics reduced weight loss and liver and pancreas damage, significantly (p < 0.05) improved glucose metabolism by regulating glucagon-like peptide-1 (GLP-1), fasting glucose and insulin levels, and increasing expression of glucose transporters. Probiotics improved hyperlipemia, inflammation, and oxidative stress by reducing the secretion of blood lipids and proinflammatory cytokines, increasing antioxidant enzymes. Metagenomic results revealed that probiotics restored gut microbiota via enhancing (reducing) the relative abundance of beneficial bacteria (harmful bacteria) and altered specific metabolic pathways in T2D mice. CKCC1, CKCC3, and CKCC4 showed excellent effects compared to CKCC2. These results indicated that probiotics potentially prevented T2D, which is strain-specific.

Discrimination and characterization of different coconut water (CW) by their phenolic composition and volatile organic compounds (VOCs) using LC-MS/MS, HS-SPME-GC-MS, and HS-GC-IMS.

Three varieties of coconut (Cocos nucifera L.) water (CW) at two maturity stages were investigated for physicochemical and nutritional properties. The profile of phenolic compounds and volatile organic compounds (VOCs) was determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), headspace solid-phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS), and headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS). Most of the properties of CW changed significantly with maturity rather than variety. The five most relevant phenolic compounds in CW were chlorogenic acid, 4-hydroxy-3,5-dimethoxycinnamic acid, L-epicatechin, and procyanidins B2 and B1. Variety played a more important role in phenolic composition than maturity, and Wenye No. 4 can be distinguished from other two varieties. Alcohols and esters were the main VOCs in CW identified by HS-GC-IMS and HS-SPME-GC-MS, respectively. Five and four compounds (VIP scores > 1) were characteristic compounds for CW by HS-GC-IMS and HS-SPME-GC-MS, respectively. The VOCs of Wenye Nos. 2 and 3 were more similar than those of Wenye No. 4. These findings could provide useful information for the selection of raw materials of CW used for different industrial purposes.

Development of protein-polyphenol particles to stabilize high internal phase Pickering emulsions by polyphenols' structure.

Protein-polyphenol colloidal particles are promising stabilizers for high internal phase Pickering emulsions (HIPPEs). However, the relationship between the structure of the polyphenols and its ability to stabilize HIPPEs has not been studied thus far. In this study, bovine serum albumin (BSA)-polyphenols (B-P) complexes were prepared, and their ability to stabilize HIPPEs was investigated. The polyphenols were bound to BSA via non-covalent interactions. Optically isomeric polyphenols formed similar bonds with BSA, whereas a greater number of trihydroxybenzoyl groups or hydroxyl groups in the dihydroxyphenyl moieties of polyphenols increased the B-P interactions. Polyphenols also reduced the interfacial tension and enhanced the wettability at the oil-water interface. The HIPPE stabilized by BSA-tannic acid complex exhibited the highest stability among the B-P complexes and resisted demixing and aggregation during centrifugation. This study promotes the potential applications of polyphenol-protein colloidal particles-stabilized HIPPEs in the food industry.

Protective effects of di-caffeoylquinic acids from Artemisia selengensis Turcz leaves against monosodium urate-induced inflammation via the modulation of NLRP3 inflammasome and Nrf2 signaling pathway in THP-1 macrophages.

Artemisia selengensis Turcz (AST) as a common vegetable is rich in di-caffeoylquinic acids (di-CQAs) and has been reported to possess multiple health benefits. However, whether di-CQAs from AST leaf extracts (ASTE) could alleviate gout inflammation is still unknown. Herein, this study explored the inhibitory mechanism of ASTE on gout inflammation in THP-1 macrophages. Results suggested that ASTE suppressed the secretion and mRNA levels of inflammatory cytokines including interleukin-18, interleukin-1ß, interleukin-6, and tumor necrosis factor-α. Pretreatment with ASTE inhibited lipopolysaccharide-induced of IκBα degradation, p65 phosphorylation and up-regulation of Nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome proteins. Moreover, ASTE inhibited monosodium urate-induced the up-regulation of active caspase-1 and interleukin-1ß, promoted nuclear factor E2-related factor2 (Nrf2) to translocate into the nucleus, reducing the generation of MSU-induced reactive oxygen species. These results suggested that ASTE alleviated gout inflammation via inhibiting NLRP3 inflammasome activation and activating Nrf2 signaling pathway. PRACTICAL APPLICATIONS: Artemisia selengensis Turcz (AST) as a common vegetable in China belongs to genus Artemisia, which are rich in di-caffeoylquinic acids. This study aimed to investigate the effect of ASTE on alleviating gout inflammation and whether NLRP3 inflammasome and Nrf2 signaling pathways are involved in the protection of ASTE against gout inflammation. Our findings are significant for developing di-CQAs from AST by-products as an effective functional food for preventing gout.

Transport and Interactions of Co-incubated Bi-functional Flavonoids through Inhibiting the Function of P-Glycoprotein (P-gp) Using KB/Multidrug-Resistant (MDR) Cells and Rat Everted Gut Sacs.

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.

UHT treatment and storage of liquid infant formula affects protein digestion and release of bioactive peptides.

Ready-to-feed liquid infant formulas (IF) were subjected to direct (D) or indirect (ID) ultra-high-temperature (UHT) treatment and then stored at 40 °C under aseptic conditions for 60-120 days simulating global transportation which accelerates the Maillard reaction. Low pasteurized and unstored IF (LP) was included as a control for the UHT treatments. Simulated infant in vitro digestion was conducted. SDS-PAGE indicated that protein aggregate formation correlated with thermal treatment, being greatest after 60 days of storage. Limited protein digestion was observed after pepsin treatment for 2 h. Beta-lactoglobulin (ß-Lg), alpha-lactalbumin (α-La) and protein aggregates remained undigested after 2 h of pepsin digestion in LP and D, but less ß-Lg and α-La remained in ID. The digestion of ß-Lg and α-La was enhanced in D and ID stored for 60 days, but aggregates remained undigested. After pepsin and pancreatin digestion, large amounts of ß-Lg remained undigested in the LP, but digestion increased after UHT treatment (ID > D) and increased further after storage for 60 and 120 days, indicating that heat treatment and storage facilitate the digestion of unaggregated proteins. No aggregates remained after pancreatin digestion of LP, D, ID and D stored for 60 days, but were present in ID stored for 60 days. Aggregates were mainly disulphide-linked, but dityrosine linkages were detected in D and ID stored for 120 days. LC-MS/MS indicated limited proteolysis arising from endogenous milk proteases prior to in vitro digestion, being highest in D. Peptide numbers increased following pepsin and further during pancreatin digestion (ß-casein > ß-Lg > ß-La), and released ß-Lg peptides, typically 5-8 amino acids in length, contained several bioactivities, e.g., dipeptidyl-peptidase IV (DPP-IV) and angiotensin converting enzyme (ACE) inhibition.

Structure-activity relationship and mechanism of flavonoids on the inhibitory activity of P-glycoprotein (P-gp)-mediated transport of rhodamine123 and daunorubicin in P-gp overexpressed human mouth epidermal carcinoma (KB/MDR) cells.

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 (↑RhoF) and nineteen flavonoids increased the uptake of DNR (↑DNRF) in KB/MDR cells with nine flavonoids overlapped. Structure-activity relationship (SAR) indicated that 8-OCH3, and 2'-OH have a negative effect on Rho and DNR transport. Whereas 5-OH, 5-OCH3, 6-OH, 7-OCH3, 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.

PET-CT and RNA sequencing reveal novel targets for acupuncture-induced lowering of blood pressure in spontaneously hypertensive rats.

Manual acupuncture (MA) can be used to manage high blood pressure; however, the underlying molecular mechanism remains unknown. To explore the mechanism of acupuncture in the treatment of hypertension, Wistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) were subjected to either MA stimulation or the corresponding sham procedure as a negative control (Sham-MA) for 1 week. PET-CT scans, transcriptomics and molecular biology were used to evaluate the effect of MA. The results show that MA can regulate blood pressure in SHRs, change the glucose metabolism of the paraventricular hypothalamus (PVH), and affect the mRNA and protein expression levels of differentially expressed genes in the PVH. These genes may lower blood pressure by regulating angiotensin, endothelial function and inflammation. These findings reveal that MA regulates multiple biological processes and genes/proteins of the PVH, and provide a solid theoretical basis for exploring the mechanisms by which MA regulates hypertension.

Lactobacillus casei-fermented blueberry pomace augments sIgA production in high-fat diet mice by improving intestinal microbiota.

Intestinal secretory immunoglobulin A (sIgA)-improving function of Lactobacillus casei-fermented blueberry pomace (FBP) was investigated in this study. Male C57BL/6 mice were fed with control diet (CD) or high-fat diet (HFD) with or without FBP supplementation. Expressions of sIgA-associated genes/proteins were evaluated by quantitative polymerase chain reaction (qPCR), western blot and enzyme-linked immunosorbent assay (ELISA). Commensal microbiota in Peyer's patches (PPs) and caecal contents were analyzed by 16S rRNA Illumina sequencing and qPCR, respectively. FBP improved sIgA production in HFD mice at mRNA and protein levels. Akkermansia and Lactobacillus in PPs of HFD mice were statistically increased by FBP. Beneficial microbiota and short-chain fatty acids (SCFAs) in caecal contents were positively correlated with caecal immunoglobulins in HFD mice. FBP showed an ability to modulate intestinal microbiota, which improved sIgA production in HFD mice, warranting the potential use of berry by-products as functional ingredients in improving the intestinal immune barrier of HFD individuals.

Fermented blueberry pomace ameliorates intestinal barrier function through the NF-κB-MLCK signaling pathway in high-fat diet mice.

The barrier-improving functions of fermented blueberry pomace (FBP) and its potential mechanism were investigated in this study. Polyphenols and the approximate composition of FBP were evaluated according to the National Standard of the People's Republic of China and the UPLC-MS system. Male C57BL/6 mice were fed a control diet (CD) or a high-fat diet (HFD) with or without FBP supplementation. Oxidative stress, inflammation, histological morphology and the expression of functional proteins in the small intestine of mice were evaluated using the enzyme linked immunosorbent assay (ELISA), quantitative polymerase chain reaction (qPCR) and western blotting. The content of protein, fat, soluble dietary fiber, insoluble dietary fiber and carbohydrates (non-dietary fiber) was 114.5 ± 1.5 g kg-1, 5.0 ± 0.2 g kg-1, 48.0 ± 0.1 g kg-1, 360.3 ± 2.2 g kg-1 and 423 g kg-1 (by difference), respectively. Thirty-six polyphenols were identified in FBP. FBP improved the growth of mice and attenuated hepatic and intestinal oxidative stress. Intestinal inflammation was significantly reduced through the decrease of tumor necrosis factor-alpha (TNF-α) and myeloperoxidase (MPO) as well as an increase of interleukin-10 (IL-10). FBP supplementation significantly improved the intestinal morphology and barrier function, potentially by mediating the NF-κB-MLCK signaling pathway. The supplementation of FBP in HFD mice enhanced the intestinal barrier function. This suggested that polyphenol-rich by-products might provide a similar health effect in HFD individuals.

Isoflavone biochanin A, a novel nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response element activator, protects against oxidative damage in HepG2 cells.

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.

Quantitative Structure⁻Activity Relationships for the Flavonoid-Mediated Inhibition of P-Glycoprotein in KB/MDR1 Cells.

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.

Structure affinity relationship and docking studies of flavonoids as substrates of multidrug-resistant associated protein 2 (MRP2) in MDCK/MRP2 cells.

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 CUMK with MK-571 in MDCK/MRP2 cells. Also, three substrates showed better CUMD in MDCK cells than did CUMRP 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'-OCH3 substituents were favourable while, 8-OCH3, 2'-OH, 3'-OCH3, 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.

Establishment and Use of Human Mouth Epidermal Carcinoma (KB) Cells Overexpressing P-Glycoprotein To Characterize Structure Requirements for Flavonoids Transported by the Efflux Transporter.

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) CUKBE (2.90 ± 0.146 µmol/g) higher than CUKBP (1.57 ± 0.129 µmol/g) were identified as P-gp substrates. Besides, 8 substrates, including tangeretin, showed a significant ( p < 0.05) CUKB (9.72 ± 1.09 µmol/g) higher than its CUKBP (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_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'-OCH3, and 4'-OCH3 are crucial for flavonoids binding to P-gp. These results provide valuable information for finding a solution to improve the absorption of flavonoids.

Attenuation of tert-Butyl Hydroperoxide ( t-BHP)-Induced Oxidative Damage in HepG2 Cells by Tangeretin: Relevance of the Nrf2-ARE and MAPK Signaling Pathways.

The current study evaluates the protective effects of tangeretin, a representative polymethoxyflavone (PMF) mainly isolated from the peels of citrus fruits, against tert-butyl hydroperoxide ( t-BHP)-induced oxidative damage in HepG2 cells and the potential mechanisms of this protection. Tangeretin suppressed t-BHP-induced oxidative damage, as evaluated by cell viability, reactive-oxygen-species (ROS) levels, lactate dehydrogenase (LDH) leakage and glutathione (GSH) levels. Further mechanistic studies showed that tangeretin up-regulated the expression of heme oxygenase 1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). Moreover, tangeretin induced antioxidant-responsive-element (ARE)-dependent luciferase activation, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation, and mitogen-activated-protein-kinase (MAPK) phosphorylation. Results in the study indicate that the protective effects of tangeretin may be at least partly due to its capacity to up-regulate the antioxidant enzymes NQO1 and HO-1 via the MAPK-Nrf2-ARE signaling pathway. Tangeretin may play an effective protective role in liver injury.

[Professor LAI Xinsheng's experience of acupuncture combined with medication for epilepsy].

Professor LAI Xinsheng's experience of acupuncture combined with medication for epilepsy is summarized, which is explained from epilepsy's etiology and pathogenesis, diagnosis and treatment of acupuncture and medication, respectively. Besides, the theoretical foundation and use instruction of acupuncture technique "tong-yuan" for epilepsy are introduced. Professor LAI highly values the adherence to etiology and pathogenesis, pays attention to syndrome differentiation and searches for the primary disease cause. He proposes the wind, phlegm, stasis and deficiency are the pathogenesis of epilepsy, and points out acupuncture could be applied during attack stage and remittent stage, but electroacupuncture should be used with caution. Regulating spirit is the key for treating epilepsy. The combination of acupuncture and medication could regulate the governor vessel and guide qi to the origin, which have significant curative effect.

Structure characteristics for intestinal uptake of flavonoids in Caco-2 cells.

Flavonoids are a large group of polyphenols and widely distributed in plant foods. Flavonoids exhibit various biological activities, such as anti-cancer, antioxidant and anti-inflammatory while poor oral bioavailability has been considered as a major hurdle in their use as functional foods. Cellular uptake and efflux of flavonoid implicates their bioavailability. To investigate the cellular uptake and efflux of flavonoids, 27 flavonoids were measured for their cellular uptake in Caco-2 cells with (CUV) and without (CU) the inhibitor of P-glycoprotein (P-gp) verapamil. Then, a quantitative structure-absorption relationship (QSAR) model containing 21 compounds as training set was obtained from their corresponding CU. The model showed good robustness and predictivity with a high cross-validation coefficient (Q2) value of 0.809 and Log of the octanol/water partition coefficient (SlogP) and atomic charge on carbon 5 (QC5) were related to flavonoid uptake. The CUV of some flavonoids were significantly (p<0.05 or p<0.01) higher than their CU, suggesting that specific flavonoids are pumped out by P-gp. The structure-affinity relationship of flavonoids as substrates of P-gp was determined with the presence of 4'-OCH3, 3'-OCH3 and the absence of 3'-OH, 3-OH and 4'-OH favorable for the affinity of flavonoids. These results provide valuable information for screening flavonoids with good absorption and low affinity with transporters.

Study of Structure and Permeability Relationship of Flavonoids in Caco-2 Cells.

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 (Papp) and their corresponding CA was poor (R² < 0.3). Most flavonoids exhibited a ratio of 0.8-1.5 for Papp A to B/Papp 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' (QC3'), molecule surface area (SlogP_V3), balance between the center of mass and position of hydrophobic region (vsurf_ID1) and solvation energy of flavonoids (E_sol). These results provide useful information for initially screening of flavonoids with high intestinal absorption.

3D-QSAR and docking studies of flavonoids as potent Escherichia coli inhibitors.

Flavonoids are potential antibacterial agents. However, key substituents and mechanism for their antibacterial activity have not been fully investigated. The quantitative structure-activity relationship (QSAR) and molecular docking of flavonoids relating to potent anti-Escherichia coli agents were investigated. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were developed by using the pIC50 values of flavonoids. The cross-validated coefficient (q(2)) values for CoMFA (0.743) and for CoMSIA (0.708) were achieved, illustrating high predictive capabilities. Selected descriptors for the CoMFA model were ClogP (logarithm of the octanol/water partition coefficient), steric and electrostatic fields, while, ClogP, electrostatic and hydrogen bond donor fields were used for the CoMSIA model. Molecular docking results confirmed that half of the tested flavonoids inhibited DNA gyrase B (GyrB) by interacting with adenosine-triphosphate (ATP) pocket in a same orientation. Polymethoxyl flavones, flavonoid glycosides, isoflavonoids changed their orientation, resulting in a decrease of inhibitory activity. Moreover, docking results showed that 3-hydroxyl, 5-hydroxyl, 7-hydroxyl and 4-carbonyl groups were found to be crucial active substituents of flavonoids by interacting with key residues of GyrB, which were in agreement with the QSAR study results. These results provide valuable information for structure requirements of flavonoids as antibacterial agents.