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.

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.

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The barrier-to-autointegration factor (<i>BAF</i>) is widely expressed in most human tissues and plays a critical role in chromatin organization, nuclear envelope assembly, gonadal development, and embryonic stem cell self-renewal. Complete loss of <i>BAF</i> has been shown to lead to embryonic lethality and gonadal defects. The <i>BAF</i> paralog, namely, barrier-to-autointegration factor 2 (<i>BANF2</i>), exhibits a testis-predominant expression pattern in both humans and mice. Unlike <i>BAF</i>, it may cause isolated male infertility. Therefore, we used the CRISPR/Cas9 system to generate <i>Banf2</i>-knockout mice to further study its function in spermatogenesis. Unexpectedly, knockout mice did not show any detectable abnormalities in histological structure of the testis, epididymis, ovary, and other tissues, and exhibited normal fertility, indicating that <i>Banf2</i> is not essential for mouse spermatogenesis and fertility.