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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.

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 degrees 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 (beta-Lg), alpha-lactalbumin (alpha-La) and protein aggregates remained undigested after 2 h of pepsin digestion in LP and D, but less beta-Lg and alpha-La remained in ID. The digestion of beta-Lg and alpha-La was enhanced in D and ID stored for 60 days, but aggregates remained undigested. After pepsin and pancreatin digestion, large amounts of beta-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 (beta-casein > beta-Lg > beta-La), and released beta-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.

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.

Intestinal secretory immunoglobulin A (sIgA)-improving function ofLactobacillus 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.AkkermansiaandLactobacillusin 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.

As a by-product of juice industry, blueberry pomace is still a rich source of phytochemicals with potential benefits for human health. However, studies about blueberry pomace utilization are insufficient. In this study, the blueberry pomace was fermented by the probiotic Lactobacillus casei and the potential function of fermented blueberry pomace (FBP) was evaluated, including the antioxidant activity, the regulation of fecal microbiota and the production of short chain fatty acids (SCFA). The results showed that FBP obtained improved antioxidant activity which was positively correlated with the content of polyphenols. The microbiota community structure was improved by FBP through inhibiting Escherichia coli, Enterococcus and the ratio of Firmicutes and Bacteroidetes as well as improving Bifidobacterium, Ruminococcus, Lactobacillus, Akkermansia and butyrate-producing bacteria. The SCFA, especially acetic, butyric and lactic acids, were remarkably increased because of FBP-supplementation. Further, UPLC-MS analysis showed that forty-six phenolic compounds were detected in FBP while only thirty-eight in non-fermented blueberry pomace (NFBP), explaining the speculation of this study that the phytochemicals in FBP might increase the gut-improving function. This study suggested that the Lactobacillus casei-fermentation was useful for utilizing blueberry pomace as a potential candidate for functional foods.