Flavonoid Aglycones Research Articles

Inhibitory effects of flavonoids on biofilm formation by Staphylococcus aureus that overexpresses efflux protein genes.

This study evaluated the efficacy of glycone (myricitrin, hesperidin and phloridzin) and aglycone flavonoids (myricetin, hesperetin and phloretin) in inhibiting biofilm formation by Staphylococcus aureus RN4220 and S.aureus SA1199B that overexpress the msrA and norA efflux protein genes, respectively. The minimum inhibitory concentration (MIC) and minimum biofilm inhibitory concentration (MBIC50 - defined as the lowest concentration that resulted in ≥50% inhibition of biofilm formation) of flavonoids were determined using microdilution in broth procedures. The flavonoids showed MIC >1024μg/mL against S.aureus RN4220 and S.aureus SA1199B; however, these compounds at lower concentrations (1-256μg/mL) showed inhibitory effects on biofilm formation by these strains. Aglycone flavonoids showed lower MBIC50 values than their respective glycone forms. The lowest MBIC50 values (1 and 4μg/mL) were observed against S.aureus RN4220. Myricetin, hesperetin and phloretin exhibited biofilm formation inhibition >70% for S.aureus RN4220, and lower biofilm formation inhibition against S.aureus SA1199B. These results indicate that sub-MICs of the tested flavonoids inhibit biofilm formation by S.aureus strains that overexpress efflux protein genes. These effects are more strongly established by aglycone flavonoids.

Time-resolved comparative metabolomes for Koji fermentation with brown-, white-, and giant embryo-rice

A time-resolved non-targeted metabolomic study towards evaluating the effects of three rice substrate types viz., white rice (WR), giant embryo rice (GER), and brown rice (BR), on Koji fermentation was performed. Notwithstanding the relatively higher proportions of metabolites in unfermented BR (BR 0>WR 0, GER 0), the relative levels of metabolic repertoire in BR Koji were marginally enhanced during 36h fermentation except those for phenolic acids, fatty acids, and vitamins. The WR Koji showed higher levels of lysophospholipids (LysoPC’s) and protease-released amino acids (WR 36>GER 36>BR 36). The higher β-glucosidase activity in GER Koji effected the increased levels of sugars and flavonoid aglycons complementing its higher antioxidant activity (GER Koji>BR Koji∼WR Koji). The present study holistically underpins the dynamic metabolomes and enzymatic states during rice Koji fermentation with varying substrate types. The present study finds applications in optimization of commercial Koji production.

Astilbin from Engelhardtia chrysolepis enhances intestinal barrier functions in Caco-2 cell monolayers

Astilbin, which is one of polyphenolic compounds isolated from the leaves of Engelhardtia chrysolepis HANCE (Chinese name, huang-qui), is available as the effective component in food and cosmetics because of its anti-oxidant and anti-inflammatory effects. The tight junction (TJ) proteins, which protect the body from foreign substances, are related to adhesion between a cell and a cell. Previously, the enhancement of TJ's functions induced by aglycones of flavonoids has been demonstrated, but the effects of the glycosides such as astilbin have not been observed yet. In this study, we investigated the effects of astilbin on the TJ's functions, and human colon carcinoma Caco-2 cell monolayers were used to evaluate the effects of astilbin on transepithelial electrical resistance (TER) value and the mRNA and proteins expressions of TJ-related molecules. Astilbin increased the TER value, mRNA expression levels of claudin-1 and ZO-2, and protein expression levels of occludin and ZO-2 in Caco-2 cells. Astilbin also increased the TER value in Caco-2 cells co-stimulated with TNF-α plus IFN-γ, and moreover upregulated the protein expression of TJ-related molecules in Caco-2 cells co-treated with TNF-α plus IFN-γ. These results suggest that astilbin can enhance the expressions of TJ-related molecules, leading to upregulation of the barrier functions in the intestinal cells.

Flavonoids from Agrimonia pilosa Ledeb: Free Radical Scavenging and DNA Oxidative Damage Protection Activities and Analysis of Bioactivity-Structure Relationship Based on Molecular and Electronic Structures.

To clarify the substantial basis of the excellent antioxidant capacity of Agrimonia pilosa Ledeb. Fourteen flavonoids were isolated and identified from Agrimonia pilosa Ledeb, seven of which have notable DPPH radical scavenging activities, i.e., catechin, luteolin, quercetin, quercitrin, hyperoside, rutin, luteolin-7-O-β-glucoside with IC50 values of 5.06, 7.29, 4.36, 7.12, 6.34, 6.36 and 8.12 µM, respectively. The DNA nicking assay showed that five flavonoids from Agrimonia pilosa Ledeb—taxifolin, catechin, hyperoside, quercitrin and rutin—have good protective activity against DNA oxidative damage. Further, we analyzed the bioactivity-structure relationship of these 14 flavonoids by applying quantum theory. According to their O-H bond dissociation enthalpy (BDE), C ring’s spin density and stable molecular structure, the relationship between their structures and radical scavenging capacities was evaluated and clarified. We found that among flavonoid aglycones from Agrimonia pilosa Ledeb, the O-H BDE of quercetin is lowest with the values of 69.02 and the O-H BDE of apigenin is highest with the values of 79.77. It is interesting that the O-H BDE value of isovitexin (78.55) with glycoside at C-6 position is lower than that of its aglycone (79.77) and vitexin (99.20) with glycoside at C-8 position. Further analysis indicated that the glycosidation of flavonoids at C-6 in the A-ring makes a more uniform distribution of spin density and improves the stability of free radicals leading to the increase in antioxidant capacity. Flavonoids with good antioxidant capacity might contribute to the pharmacological effects of Agrimonia pilosa Ledeb.

Glucosylation of flavonol and flavanones by Bacillus cyclodextrin glucosyltransferase to enhance their solubility and stability.

Enzymatically modified isoquercitrin (EMIQ), oligoglucosyl naringenin-7-(glucose [G]), and oligoglucosyl hesperetin (H)-7-G were produced via oligoglucosylation of quercetin-3-glucose, naringenin-7-G (prunin), and H-7-G, respectively, by cyclodextrin glucosyltransferase from Bacillus macerans. The aim was to explore the oligoglucosylation and the resulting changes in physicochemical properties. Water solubility of EMIQ, oligoglucosyl prunin, and oligoglucosyl H-7-G enormously increased in comparison with that of their aglycones. Glycosylation of an aglycone generally enhances its solubility. Resistance of the aglycones to oxidative degradation by the Cu2+ ion was strongly increased by the oligoglucosylation. This is probably because oligoglucosylation may protect sensitive parts of an aglycones molecule from the Cu2+ oxidation. Only EMIQ maintained its structure during thermal treatment much longer than quercetin did. Degradation of flavonoid aglycones by ultraviolet light C irradiation at 254nm was not affected, and their antioxidant activities gradually decreased with the greater extent of oligoglucosylation.

Passive Intestinal Absorption of Representative Plant Secondary Metabolites: A Physicochemical Study.

Natural products are generally ingested as part of traditional herbal decoctions or in the current diet. However, in natural product research, the bioavailability of secondary metabolites is often poorly investigated. In this work, a systematic study was carried out in order to highlight the physicochemical parameters that mainly influence the passive intestinal absorption of natural products. For this, a representative set of natural products including alkaloids, coumarins, flavonoid aglycones and glycosides, and carboxylic acids was selected and their physicochemical properties were predicted using relevant Volsurf+ descriptors. The chemical space obtained with this unbiased method was then correlated with experimental passive intestinal permeability data, which highlighted the main influence of lipophilicity, global hydrophilicity, size, and the ionisation state on passive intestinal absorption of natural products. Since the pH range encountered in the intestine is wide, the influence of the ionisation was investigated deeper experimentally. The ionisation state of weakly ionisable natural products, such as flavonoid aglycones, alkaloids, and carboxylic acids, was found to prevent the passive intestinal absorption of such natural products completely. In addition, the impact of solubility issues on passive permeability results was evaluated in cases of poorly water-soluble natural products, such as flavonoid aglycones and coumarins. The biomimetic fasted state simulated fluid-version 2 was found to improve the apparent solubility of such poorly soluble natural products without influencing their permeability behaviours. The use of such a solubilising buffer was found to be well adapted to the hexadecane membrane-parallel artificial membrane permeability assay and can circumvent the solubility issues encountered with poorly soluble natural products in such an assay.

Efficient Preparation of Ephedrine Alkaloids-free Ephedra Herb Extract and Its Antitumor Effect and Putative Marker Compound.

Ephedra Herb is a crude drug for the treatment of headache, bronchial asthma, nasal inflammation, and the common cold. Although it has been considered that ephedrine alkaloids (EAs) are the principal active ingredients of Ephedra Herb, EAs are known to induce palpitations, hypertension, insomnia, and dysuria as major side effects. Therefore, the administration of EAs-containing drugs to patients with cardiovascular-related diseases is strongly contraindicated. Previously, we isolated herbacetin 7-O-neohesperidoside from Ephedra Herb. In addition, we found that herbacetin, a flavonoid aglycone in Ephedra Herb, had antiproliferative and analgesic effects. Therefore, the prospect of preparing safer natural medicines without the adverse effects associated with EAs was appealing. In this symposium review, to achieve the aim of producting a clinically useful Ephedra Herb extract with none of the adverse effects associated with EAs, I present an efficient preparation method of EAs-free Ephedra Herb extract, together with its chemical composition, antiproliferative effects, and a putative marker for quality control.

Interaction of quercetin and its metabolites with warfarin: Displacement of warfarin from serum albumin and inhibition of CYP2C9 enzyme.

Flavonoids are ubiquitous molecules in nature with manifold pharmacological effects. Flavonoids interact with several proteins, and thus potentially interfere with the pharmacokinetics of various drugs. Though much is known about the protein binding characteristics of flavonoid aglycones, the behaviour of their metabolites, which are extensively formed in the human body has received little attention. In this study, the interactions of the flavonoid aglycone quercetin and its main metabolites with the albumin binding of the oral anticoagulant warfarin were investigated by fluorescence spectroscopy and ultrafiltration. Furthermore, the inhibitory effects of these flavonoids on CYP2C9 enzyme were tested because the metabolic elimination of warfarin is catalysed principally by this enzyme. Herein, we demonstrate that each tested flavonoid metabolite can bind to human serum albumin (HSA) with high affinity, some with similar or even higher affinity than quercetin itself. Quercetin metabolites are able to strongly displace warfarin from HSA suggesting that high quercetin doses can strongly interfere with warfarin therapy. On the other hand, tested flavonoids showed no or weaker inhibition of CYP2C9 compared to warfarin, making it very unlikely that quercetin or its metabolites can significantly inhibit the CYP2C9-mediated inactivation of warfarin.

Quantification of Flavonoids in Brazilian Orange Peels and Industrial Orange Juice Processing Wastes

The flavonoid content in orange peels of different Brazilian citrus varieties such as bahia, lima, lima-of-persian, morcote, pera, ponkan, seleta, cravo, kinkan and pomelo was assessed. Industry processing juice wastes such as bagasse, bagasse residues, animal feeding bagasse, pulp WEUE and CORE-wash were also analyzed. The HPLC analysis indicates that the most abundant flavonoids found in these Brazilian citrus peels are hesperidin and naringin. The solvents used are selective for flavonoid extraction, and depending on their polarity, glycoside or aglycone flavonoids are extracted. The use of multivariate analysis shows that DMSO is the best solvent to extract glycosides flavanones while hexane displays high selectivity in the extraction of polymethoxylated flavones. The flavonoids present in the orange wastes, obtained at different stages of the industrial processing, are qualitative and quantitatively different. The identification and quantification of the flavonoid composition in each Brazilian citrus variety were evaluated and allowed the selection of the best solvent for the extraction of each specific class of flavonoids. These compounds were found to be more abundant in the fruit peels than in their juices, revealing their great industrial potential. The residual portion of the processing juices is also rich in flavonoids, depending on the processing step.

The Potential for Climate Impacts from Widespread Deployment of Utility-Scale Solar Energy Installations: An Environmental Remote Sensing Perspective

Sutherlandia frutescens is a popular South African plant commercially available in a range of formulations. However, reference standards for quality and stability assessment are lacking. This work reports the development and validation of a reversed phase HPLC method for the analysis of flavonoid glycosides and their corresponding aglycones in S. frutescens products. Five materials containing either leaf powder (LP) or spray-dried aqueous extract (SDAE) of S. frutescens were analysed for flavonoid content. A primary objective was to isolate non-commercially available flavonoid glycoside compounds (sutherlandins) for use as reference standards. Sutherlandins A, B, C and D were successfully isolated, and used, with other flavonoid compounds for HPLC assay development. The developed HPLC method was linear in the range of 0.2 to 60 μg/ml for quercitrin; 0.2 to 120 μg/ml for quercetin and kaempferol; 0.2 to 200 μg/ml for rutin and kaempferol-3-O-rutinoside; 4 to 180 μg/ml for sutherlandins A and D; and 4 to 200 μg/ml for sutherlandins B and C. Percentage content of sutherlandins A, B, C and D, quercetin and kaempferol in different plant materials were significantly different (P<0.001). The developed HPLC method is simple, precise and robust; and can be employed for the simultaneous determination of flavonoid glycosides and aglycones for quality control of S. frutescens products.

Chemical Investigation of Wrightia tinctoria

The systematic chemical analysis of leaves of Wrightia tinctoria were found to contain two flavonoid glycosides Kaempferol 3-O-rhamnoside and Quercetin 3-O-sophoroside and two flavonoid aglycone Kaempferol and Quercetin. The detailed UV 1H 13C NMR and Mass spectral data confirm the characterization of the above compounds. All these compounds are reported first time from the leaves of Wrightia tinctoria.

Inhibitory Activities of Antioxidant Flavonoids from &lt;i&gt;Tamarix gallica&lt;/i&gt; on Amyloid Aggregation Related to Alzheimer’s and Type 2 Diabetes Diseases

The prevention of amyloid aggregation is promising for the treatment of age-related diseases such as Alzheimer's (AD) and type 2 diabetes (T2D). Ten antioxidant flavonoids isolated from the medicinal halophyte Tamarix gallica were tested for their amyloid aggregation inhibition potential. Glucuronosylated flavonoids show relatively strong inhibitory activity of Amyloid β (Aβ) and human islet amyloid polypeptide (hIAPP) aggregation compared to their aglycone analogs. Structure-activity relationship of the flavonoids suggests that the catechol moiety is important for amyloid aggregation inhibition, while the methylation of the carboxyl group in the glucuronide moiety and of the hydroxyl group in the aglycone flavonoids decreased it.

The anti-inflammatory activity of dietary flavonoid aglycones and their glucuronidated metabolites in human neutrophils (PMNs) and human umbilical vein endothelial cells (HUVECs)

The anti-inflammatory activity of dietary flavonoid aglycones and their glucuronidated metabolites in human neutrophils (PMNs) and human umbilical vein endothelial cells (HUVECs)

Metabolism of Quercetin and Naringenin by Food-Grade Fungal Inoculum, Rhizopus azygosporus Yuan et Jong (ATCC 48108).

Rhizopus azygosporus Yuan et Jong (ATCC 48108), a starter culture for fermented soybean tempeh, produces β-glucosidases that cleave flavonoid glycosides into aglycones during fermentation. However, recent data suggest that fermentation of a flavonoid glycoside-rich extract with this strain did not result in the production of aglycones. Thus, in this paper, flavonoid metabolism of this strain was investigated. Incubation of flavonoid aglycones, naringenin and quercetin, with R.azygosporus resulted in the production of flavonoid glucosyl-, hydroxyl-, and sulfo-conjugated derivatives. Naringenin was completely metabolized within 96 h into eriodictyol sulfate and eriodictyol glucoside, whereas quercetin was partially metabolized into quercetin glucoside, diglucoside, sulfate, and glucosyl-sulfate. Most of these metabolites were found to be excreted by the fungi into the culture medium. Toxicity analysis revealed that incubation with both quercetin and naringenin did not exert inhibitory effects on fungal growth. This study presents an interesting mechanism of fungal detoxification of flavonoids in foods.

In vitro bioavailability and cellular bioactivity studies of flavonoids and flavonoid-rich plant extracts: questions, considerations and future perspectives.

In vitro techniques are essential in elucidating biochemical mechanisms and for screening a wide range of possible bioactive candidates. The number of papers published reporting in vitro bioavailability and bioactivity of flavonoids and flavonoid-rich plant extracts is numerous and still increasing. However, even with the present knowledge on the bioavailability and metabolism of flavonoids after oral ingestion, certain inaccuracies still persist in the literature, such as the use of plant extracts to study bioactivity towards vascular cells. There is therefore a need to revisit, even question, these approaches in terms of their biological relevance. In this review, the bioavailability of flavonoid glycosides, the use of cell models for intestinal absorption and the use of flavonoid aglycones and flavonoid-rich plant extracts in in vitro bioactivity studies will be discussed. Here, we focus on the limitations of current in vitro systems and revisit the validity of some in vitro approaches, and not on the detailed mechanism of flavonoid absorption and bioactivity. Based on the results in the review, there is an apparent need for stricter guidelines on publishing data on in vitro data relating to the bioavailability and bioactivity of flavonoids and flavonoid-rich plant extracts.

Application of microbial alkaloid prodigiosin as a potent matrix for the MALDI mass spectrometry analysis of low-molecular-weight plant antioxidants

Microbial alkaloid prodigiosin is proposed as a new effective matrix for the analysis of low-molecular- weight plant antioxidants by MALDI mass spectrometry in the negative ion detection mode. It is demonstrated that the physicochemical characteristics of prodigiosin, such as ability to activate ionization/ desorption of analyte, high absorption coefficient at the working wavelengths of lasers, good solubility in solvents used for analytes, uniformity of crystallization on the target, stability under working conditions, and the absence of interfering peaks of fragment and cluster ions, are consistent with the recommendations for effective matrices. Prodigiosin as a matrix ensures the high-resolution detection of various plant antioxidants in complex mixtures. The obtained mass spectra of flavonoid aglycones were characterized by high quality (signal-to-noise ratio higher than 103) and reproducibility. The use of prodigiosin for analyzing a complex preparation of plant antioxidants ensures the simultaneous recording and interpretation of more than two dozens of ions corresponding to various antioxidants with the molecular weights of 100–500 Da.

Deep eutectic solvents as green media for extraction of flavonoid glycosides and aglycones from Platycladi Cacumen

Deep eutectic solvents (DESs) are emerging as alternatives to conventional ionic liquids and organic solvents due to their unique advantages. In the present study, the tuneability of DESs as tailor-made solvents to efficiently extract polar and non-polar bioactive compounds from Platycladi Cacumen was detailedly investigated. Totally 12 types of choline chloride-, betaine-, and l-proline-based DESs were synthesized for initial screening, and extraction conditions was optimized by single-factor experiment. Experiments with different DESs and principal components analysis demonstrated that the extractability of both flavonoid glycosides and aglycones was greater with certain designed DESs than conventional solvents. In addition, the water content in DESs led to significantly different extraction yields of flavonoid compounds. The target compounds were recovered from DESs by macroporous resin LX-38 with a satisfactory yield between 77.44% and 98.92%. The knowledge acquired in this study could contribute to further DES application in extraction of bioactive compounds from natural sources.

Methanolic extract of Agerantum conyzoides exhibited toxicity and growth disruption activities against Anopheles gambiae sensu stricto and Anopheles arabiensis larvae.

BackgroundVector control remains the mainstay to effective malaria management. The negative implications following persistent application of synthetic insecticides geared towards regulation of mosquito populations have necessitated prospection for ecofriendly effective chemistries. Plant-derived compounds have the potential to control malaria-transmitting mosquito populations. Previously, Agerantum conyzoides extracts have demonstrated toxicity effects on disease-transmitting mosquitoes. However, their efficacy in controlling Afrotropical malaria vectors remains unclear. Herein, the toxicity and growth disruption activities of crude methanolic leaf extract of A. conyzoides on Anopheles gambiae sensu stricto and An. arabiensis larvae were assessed. MethodsLate third (L3) instars of An. gambiae s.s and An. arabiensis larvae were challenged with increasing doses of crude methanolic extract of A. conyzoides. The larval mortality rates were recorded every 24 h and the LC50 values determined at their associated 95% confidence levels. ANOVA followed by Post-hoc Student-Newman-Keuls (SNK) test was used to compare results between treatment and control groups. Phytochemical profiling of the extract was performed using standard chemical procedures.ResultsTreatment of larvae with the methanolic extract depicted dose-dependent effects with highest mortality percentages of ≥ 69% observed when exposed with 250 ppm and 500 ppm for 48 h while growth disruption effects were induced by sublethal doses of between 50–100 ppm for both species. Relative to experimental controls, the extract significantly reduced larval survival in both mosquito species (ANOVA, F(8,126) = 43.16776, P < 0.001). The LC50 values of the extract against An. gambiae s.s ranged between 84.71–232.70 ppm (95% CI 81.17–239.20), while against An. arabiensis the values ranged between 133.46–406.35 ppm (95% CI 131.51–411.25). The development of the juvenile stages was arrested at pupal-larval intermediates and adult emergence. The presence of alkaloids, aglycone flavonoids, triterpenoids, tannins and coumarins can partly be associated with the observed effects.ConclusionThe extract displayed considerable larvicidal activity and inhibited emergence of adult mosquitoes relative to experimental controls, a phenomenon probably associated with induced developmental hormone imbalance. Optimization of the bioactive compounds could open pathways into vector control programmes for improved mosquito control and reduced malaria transmission rates.

Structure-solubility relationships and thermodynamic aspects of solubility of some flavonoids in the solvents modeling biological media

Flavonoids play an important role for our health. Solubility is one of the most important physicochemical properties of bioactive compounds. In order to get more information about physicochemical properties of flavonoids, this paper carried out three aspects of research focused on solubility as following: the relationship between structure and solubility of flavonoid aglycones in water and 1-octanol, the thermodynamic aspects of solubility processes and the thermodynamic functions of transfer processes of the investigated compounds from water to 1-octanol. The solubility of 13 flavonoid aglycones was determined using the isothermal saturation method. The changes of thermodynamic functions were calculated using the Van't Hoff equation and analyzed by a diagram method. The results indicated that an OH or OCH3 substituent on ring B, the ring B connection position, the bond order between C2 and C3 (C2C3 or C2C3), and an OH substituent at 3 position could influence the solubility of flavonoids. The modified Apelblat equation fitted well the experimental solubility data in water and 1-octanol. Dissolution processes of studied compounds in water are mainly enthalpy determined. In 1-octanol, the dissolution processes of chrysin, apigenin, kampferol and morin hydrate are entropy-driven process, while other compounds are enthalpy determined. The transfer processes of the investigated compounds from water to 1-octanol are spontaneous. In this case, the solubility in water is one of the most important factors influencing driving force of the transfer process. These results may provide a better understanding of biopharmaceutical properties of flavonoids and might be important for further studies on the formulation development of flavonoids.

Comparative assessment of phytochemical profiles, antioxidant and antiproliferative activities of Sea buckthorn (Hippophaë rhamnoides L.) berries

Phytochemical profiles, antioxidant and antiproliferative activities of berry extracts were evaluated and compared in four subspecies of Sea buckthorn (Hippophaë rhamnoides L.). Among the subspecies, Hippophaë rhamnoides L. subsp. sinensis exhibited highest total phenolics content (38.7±1.3mgGA equiv./g DW) and corresponding total antioxidant activity. Whereas maximum cellular antioxidant and antiproliferative activities were determined in Hippophaë rhamnoides L. subsp. yunnanensis. Total antioxidant activity was significantly associated to total phenolics, isorhamnetin-3-rutinoside and isorhamnetin-3-glucoside. The cellular antioxidant activity and antiproliferative activity of phytochemicals were fairly correlated to phenolic acids and flavonoid aglycones. Lower median effective dose (EC50) of individual compounds against human liver cancer HepG2 cells proliferation studies confirmed the better correlation between antiproliferative activity of Sea buckthorn extracts and flavonoid aglycones, including isorhamnetin, quercetin and kaempferol.