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• The role of flavonoids in mechanisms of acclimation to high solar radiation was analysed in Ligustrum vulgare and Phillyrea latifolia, two Mediterranean shrubs that have the same flavonoid composition but differ strikingly in their leaf morphoanatomical traits. • In plants exposed to 12 or 100% solar radiation, measurements were made for surface morphology and leaf anatomy; optical properties, photosynthetic pigments, and photosystem II efficiency; antioxidant enzymes, lipid peroxidation and phenylalanine ammonia lyase; synthesis of hydroxycinnamates and flavonoids; and the tissue-specific distribution of flavonoid aglycones and ortho-dihydroxylated B-ring flavonoid glycosides. • A denser indumentum of glandular trichomes, coupled with both a thicker cuticle and a larger amount of cuticular flavonoids, allowed P. latifolia to prevent highly damaging solar wavelengths from reaching sensitive targets to a greater degree than L. vulgare. Antioxidant enzymes in P. latifolia were also more effective in countering light-induced oxidative load than those in L. vulgare. Consistently, light-induced accumulation of flavonoids in L. vulgare, particularly ortho-dihydroxylated flavonoids in the leaf mesophyll, greatly exceeded that in P. latifolia. • We conclude that the accumulation of flavonoid glycosides associated with high solar radiation-induced oxidative stress and, hence, biosynthesis of flavonoids appear to be unrelated to 'tolerance' to high solar radiation in the species examined.

Summary With changes in complex environments, plants, especially their leaves, are constantly adapting. Aquatic plants face more diverse and harsh survival situations. However, their adaptive mechanisms are largely unknown. Euryale ferox is a floating leaf aquatic plant characterized by large and rapidly expanding leaves that serve as a model for studying the environmental adaptability of aquatic plants. Single‐cell transcriptional maps of key developmental nodes in E. ferox leaves were constructed using single‐cell technology. The environmental adaptation strategies of E. ferox leaves exhibited significant differences when transitioning from submergence to emergence from water. Epidermis cells (ECs) preferentially differentiated during the submerged stage, involving the expression of numerous ribosomal proteins and plant immunity genes. During the floating stage, a significant number of mesophyll cells and hydathode cells undergo differentiation, with energy metabolism genes exhibiting high activity. Furthermore, the specific accumulation of flavonoid C‐glycosides (FCGs) in ECs was another adaptation exhibited by E. ferox leaves. The genes involved in FCG biosynthesis demonstrated EC‐specific expression, and a crucial C‐glycosyltransferase gene, EfCGT1, was characterized. A transcriptional regulatory network was constructed in which the EfZHD17–EfZHD19 module regulated EfCGT1 activity. To our knowledge, this work is the first to elucidate the molecular mechanisms by which E. ferox adapts to aquatic ecology at a single‐cell resolution, offering a model for aquatic plants.

Flavonoids possess diverse bioactivity and potential medicinal values. Glycosylation of flavonoids, coupling flavonoid aglycones and glycosyl groups in conjugated form, can change the biological activity of flavonoids, increase water solubility, reduce toxic and side effects, and improve specific targeting. Therefore, it is desirable to synthesize various flavonoid glycosides for further investigation on their medicinal values. Compared with chemical glycosylations, biotransformations catalyzed by uridine diphospho-glycosyltransferases provide an environmentally friendly way to construct glycosidic bonds without repetitive chemical synthetic steps of protection, activation, coupling, and deprotection. In this review, we will summarize the existing knowledge on the biotechnological glycosylation reactions either in vitro or in vivo for the synthesis of flavonoid O- and C-glycosides and other rare analogs.Key points• Flavonoid glycosides usually show improved properties compared with their flavonoid aglycones.• Chemical glycosylation requires repetitive synthetic steps and purifications.• Biotechnological glycosylation reactions either in vitro or in vivo were discussed.• Provides representative synthetic examples in detail.

The role of the 6″-OH (ω-OH) group in the antioxidant activity of flavonoid glycosides has been largely overlooked. Herein, we selected quercitrin (quercetin-3-O-rhamnoside) and isoquercitrin (quercetin-3-O-glucoside) as model compounds to investigate the role of the 6″-OH group in several antioxidant pathways, including Fe2+-binding, hydrogen-donating (H-donating), and electron-transfer (ET). The results revealed that quercitrin and isoquercitrin both exhibited dose-dependent antioxidant activities. However, isoquercitrin showed higher levels of activity than quercitrin in the Fe2+-binding, ET-based ferric ion reducing antioxidant power, and multi-pathways-based superoxide anion-scavenging assays. In contrast, quercitrin exhibited greater activity than isoquercitrin in an H-donating-based 1,1-diphenyl-2-picrylhydrazyl radical-scavenging assay. Finally, in a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl assay based on an oxidatively damaged mesenchymal stem cell (MSC) model, isoquercitrin performed more effectively as a cytoprotector than quercitrin. Based on these results, we concluded that (1) quercitrin and isoquercitrin can both indirectly (i.e., Fe2+-chelating or Fe2+-binding) and directly participate in the scavenging of reactive oxygen species (ROS) to protect MSCs against ROS-induced oxidative damage; (2) the 6″-OH group in isoquercitrin enhanced its ET and Fe2+-chelating abilities and lowered its H-donating abilities via steric hindrance or H-bonding compared with quercitrin; and (3) isoquercitrin exhibited higher ROS scavenging activity than quercitrin, allowing it to improve protect MSCs against ROS-induced oxidative damage.

Clostridium butyricum inhabits various anoxic environments, including soil and the human gut. Here, this common bacterium comes into contact with abundant plant-derived flavonoids. Metabolization of these bioactive polyphenols has been studied in recent years, particularly focusing on gut bacteria due to the proposed health-promoting properties of these dietary constituents. Based on an initial report in 1997 on eriodictyol degradation (Miyake et al. 1997, J Agric Food Chem, 45:3738–3742), the present study systematically investigated C. butyricum for its ability to convert a set of structurally diverse flavonoids. Incubation experiments revealed that C. butyricum deglycosylated flavonoid O -glucosides but only when glucose was absent. Moreover, aglycone members of flavone, flavanone, dihydrochalcone, and flavanonol subclasses were degraded. The C-ring cleavage of the flavanones, naringenin and eriodictyol, was stereospecific and finally resulted in formation of the corresponding hydroxyphenylpropionic acids. Stereospecific C-ring cleavage of the flavanonol taxifolin led to taxifolin dihydrochalcone. C. butyricum did neither cleave flavonols and isoflavones nor catalyze de-rhamnosylation, demethylation, or dehydroxylation of flavonoids. Genes encoding potential flavonoid-metabolizing enzymes were detected in the C. butyricum genome. Overall, these findings indicate that C. butyricum utilizes flavonoids as alternative substrates and, as observed for the dihydrochalcone phloretin, can eliminate growth-inhibiting flavonoids through degradation. Key points • Clostridium butyricum deglycosylated flavonoid O-glucosides. • Clostridium butyricum converted members of several flavonoid subclasses. • Potential flavonoid-metabolizing enzymes are encoded in the C. butyricum genome.

In this study, we aimed to determine the chemical constituents of M. seguinii, which led to the isolation and identification of 26 compounds. Three new prenylated dihydrobenzofurans [myrsinoic acids I (1), J (2), and K (3)] and a new flavonoid glycoside, mearnsetin 3-O-α-L-arabinopyranoside (4), were discovered, and the absolute configuration of the known compound, myrsinoic acid B (5), was re-established. To ensure the structural accuracy of these compounds, comprehensive spectroscopic analyses were performed, including one- and two-dimensional nuclear magnetic resonance spectroscopy, mass spectrometry, and circular dichroism spectroscopy. In addition, computational analysis methods such as density functional theory (DFT)-based Electronic Circular Dichroism (ECD) simulations and Gauge-Including Atomic Orbitals (GIAOs) 1H and 13C NMR chemical shift calculations with DP4+ probability analysis were utilised to further support the structural assignments.

Flavonoid glycosides exhibit compromised bioavailability due to low membrane permeability. To address this limitation, we acetylated flavonoids through enzymatic reactions to increase bioavailability. This study first reported that Hesperetin-7- O -glucoside (Hes-7-G) was acetylated by galactoside acetyltransferase (GAT), and the apparent permeability ( P app ) of the Caco-2 monolayer was increased by 69%, indicating the acetylated Hes-7-G application potential to improve bioavailability. Subsequently, we designed GAT mutants through comprehensive computational and experimental methods to improve the acetylation efficiency and elucidate the catalytic mechanism. Molecular Dynamics (MD) simulations found that Tyr483 and Met127 are key residues that control flavonoid binding through dynamic van der Waals interactions, while His115 and Thr113 mediated proton transfer accounts for 85–90% of the catalytic activity. Rational substitution of Pro148 with alanine (P148A) increased the flexibility of the cofactor binding ring and increased the catalytic efficiency ( K cat /K M ) by 21%. Average non-covalent interaction (aNCI) analysis revealed that regional selectivity in the glucose portion was controlled by hydrophobic interactions with Tyr483 and hydrogen bonding with Gly125, and rhamnose substitution caused spatial conflict. This work deciphered the structure-activity relationship of GAT, established a framework for protein engineering, and highlighted enzyme-driven acetylation as a sustainable strategy for optimizing flavonoid pharmacokinetics. Key points • Engineered acetyltransferase enhances flavonoid glycoside absorption. • P148A mutation improves catalytic efficiency. • Insight into the catalytic mechanism of GAT by flavonoid glycoside substrates.

Didymin (isosakuranetin 7-O-rutinoside) is an orally bioactive dietary flavonoid glycoside first found in citrus fruits. Traditionally, this flavonoid has long been used in Asian countries as a dietary antioxidant. Recent studies have provided newer insights into this pleiotropic compound, which could regulate multiple biological activities of many important signaling molecules in health and disease. Emerging data also presented the potential therapeutic application of dietary flavonoid glycoside didymin against cancer, neurological diseases, liver diseases, cardiovascular diseases, and other diseases. In this review, we briefly introduce the source and extraction methods of didymin, and summarize its potential therapeutic application in the treatment of various diseases, with an emphasis on molecular targets and mechanism that contributes to the observed therapeutic effects. The dietary flavonoid didymin can be used to affect health and disease with multiple therapeutic targets, and it is anticipated that this review will stimulate the future development of this potential dietary medicine.

α-L-rhamnosidases play a key role in the metabolism and biodegradation of dietary flavonoid glycosides. We have developed a novel microplate spectrophotometric method to rapidly evaluate the conversion rates and substrate selectivities of mesophilic α-L-rhamnosidases towards citrus flavanone diglycosides by combining with a high-active and thermophilic β-D-glucosidase based on UV-visible spectral differences between citrus flavanone diglycosides and the corresponding aglycones under alkaline conditions. Furthermore, catalytic activities and enzyme kinetics of four α-L-rhamnosidases from human gut bacteria on various dietary flavonoid glycosides with different glycosidic bonds from various subclasses have been explored by HPLC. The α-L-rhamnosidase BtRha78A specifically removed the rhamnose group from the flavones, flavanones and flavonols diglycosides with the α-1,6 glycosidic bonds. Moreover, BtRha78A displayed higher catalytic activities on the rutinose group at 7-OH of the aglycones than at 3-OH. HFM-RhaA preferred to catalyze the flavones, flavanones and dihydrochalcones diglycosides with the α-1,2 glycosidic linkages at the 7-OH. However, this enzyme also showed high catalytic activity on the flavonol diglycoside rutin with the α-1,6 glycosidic bonds at the 3-OH. HFM-RhaC exhibited certain hydrolytic abilities towards all flavonoid diglycosides, and displayed higher activities on the flavonoid diglycosides with the α-1,6 glycosidic bonds. HFM-Rha78 weakly hydrolyzed the flavones, flavanones and dihydrochalcones diglycosides with the α-1,2 glycosidic bonds, and the flavonols diglycosides with α-1,6 glycosidic bonds. All four α-L-rhamnosidases from human gut bacteria did not exhibit catalytic activity towards the flavonoid glycosides with the α-1 glycosidic bonds. It was revealed that the α-L-rhamnosidases from human gut bacteria possessed diverse substrate selectivity on dietary flavonoid diglycosides. The structural basis for the specificity of BtRha78A on the flavonoid diglycosides with α-1,6 glycosidic bonds and the preference of HFM-RhaA on the flavonoid diglycosides with α-1,2 glycosidic bonds have been analyzed by molecular docking.

The aim of this study was to explore the role of p-coumaroyl in the antioxidant and cytoprotective effects of flavonoid glycosides. The antioxidant effects of astragalin and tiliroside were compared using ferric ion reducing antioxidant power, DPPH• scavenging, ABTS•+ scavenging, •O2– scavenging, and Fe2+-chelating assays. The results of these assays revealed that astragalin and tiliroside both exhibited dose-dependent activities; however, tiliroside exhibited lower IC50 values than astragalin. In the Fe2+-chelating assay, tiliroside gave a larger shoulder-peak at 510 nm than astragalin, and was also found to be darker in color. Both of these compounds were subsequently evaluated in a Fenton-induced mesenchymal stem cell (MSC) damaged assay, where tiliroside performed more effectively as a cytoprotective agent than astragalin. Tiliroside bearing a 6′′-O-p-coumaroyl moiety exhibits higher antioxidant and cytoprotective effects than astragalin. The 6′′-O-p-coumaroyl moiety of tiliroside not only enhances the possibility of electron-transfer and hydrogen-atom-transfer-based multi-pathways, but also enhances the likelihood of Fe-chelating. The p-coumaroylation of the 6\"-OH position could therefore be regarded as a potential approach for improving the antioxidant and cytoprotective effects of flavonoid glycosides in MSC implantation therapy.