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Dimeric flavonoids, also called biflavonoids, are bioactive compounds that exhibit various activities described in the literature, including antibacterial, antifungal, antiviral, anti-inflammatory, analgesic, antioxidant, vasorelaxant, and anticancer properties. This work focuses on the anticancer action of naturally occurring dimeric flavonoids against prostate and breast cancer, as well as on the mechanisms of action involved in their activity and presents the most current information on this subject in the literature. In the present review, we summarize the latest findings on the antiproliferative activity of 33 dimeric flavonoid-based compounds selected from recently published studies. The tests conducted were in silico and in vitro and demonstrated the cytotoxic activity potential of biflavonoids against prostate and breast tumor cells. Biflavonoids were capable of interfering with the migration and replication of cancer cells and their mechanism of action is related to cell death pathways, especially apoptosis, necrosis, and ferroptosis. These compounds decreased mitochondrial membrane potential and significantly increased intracellular levels of reactive oxygen species (ROS). Additionally, they significantly upregulated the expression of p21, Bax, and cleaved caspase-3, while downregulating Bcl-2 and caspase-3 levels, indicating their cell death mechanism of action is through the Bcl-2/Bax/cleaved caspase-3 pathway and cell cycle arrest. The biflavonoids here related have shown promising anticancer activity and are considered potential drug candidates for prostate and breast cancer treatment. [ABSTRACT FROM AUTHOR]

The leaves of Araucaria cunninghamii are known to be nonedible and toxic. Previous studies have identified biflavones in various Araucaria species. This study aimed to investigate the in vitro cytotoxicity of the isolated compounds from Araucaria cunninghamii after metabolomics and network pharmacological analysis. Methanol extract of Araucaria cunninghamii leaves was subjected to bioassay‐guided fractionation. The active fraction was analyzed using LC‐HRMS, through strategic database mining, by comparing the data to the Dictionary of Natural Products to identify 12 biflavones, along with abietic acid, beta‐sitosterol, and phthalate. Eight compounds were screened for network pharmacology study, where in silico ADME analysis, prediction of gene targets, compound‐gene‐pathway network and hierarchical network analysis, protein–protein interaction, KEGG pathway, and Gene Ontology analyses were done, that showed PI3KR1, EGFR, GSK3B, and ABCB1 as the common targets for all the compounds that may act in the gastric cancer pathway. Simultaneously, four biflavones were isolated via chromatography and identified through NMR as dimeric apigenin with varying methoxy substitutions. Cytotoxicity study against the AGS cell line for gastric cancer showed that AC1 biflavone (IC50 90.58 μM) exhibits the highest cytotoxicity and monomeric apigenin (IC50 174.5 μM) the lowest. Besides, the biflavones were docked to the previously identified targets to analyze their binding affinities, and all the ligands were found to bind with energy ≤−7 Kcal/mol. [ABSTRACT FROM AUTHOR]

The biflavonoid extraction from ginkgo (Ginkgo biloba L.) leaves using solvent-based extraction with 70% ethanol, alone and in combination with enzyme-assisted, ultrasound-assisted, mechanical-assisted, and chemically assisted methods was investigated and the influence of extraction duration was explored. The total content of polyphenols, flavonoids, and phenolic acids in the extracts was determined spectrophotometrically, while individual biflavonoids were identified and quantified using HPLC-DAD. Amentoflavone, bilobetin, ginkgetin, isoginkgetin, and sciadopitysin were identified in all our extracts. Among these, sciadopitysin emerged as the most prevalent biflavonoid with an amount above 1 mg g−1 dw, followed by isoginkgetin. Comparative analysis of the extraction methods revealed that, except for chemically assisted extraction, similar levels of compounds were obtained after 45 min of extraction. However, enzymatic (EAE) and mechanical-assisted extraction (MAE) exhibited significantly higher individual (EAE: 19–41% higher; MAE: 22–67% higher) and total biflavonoid (EAE: 29% higher; MAE 50% higher) levels after just 5 min, suggesting their potential to abbreviate extraction duration and facilitate the efficient retrieval of target compounds. However, as extraction efficiency varies between individual biflavonoids, our findings also underscore the importance of considering specific compounds and extraction kinetics in the optimization of ginkgo leaf extraction processes. [ABSTRACT FROM AUTHOR]

AbstractThe inhibition of carbohydrate digestion is an effective strategy to treat diabetes mellitus and its complications. In recent years, natural products, especially the monoflavonoids, have been widely reported to be beneficial in the prevention of diabetes through delaying starch digestion. However, the value of the biflavonoids, another important class of natural compounds, with potential inhibitory effects against carbohydrate-hydrolyzing enzymes, has not yet been elucidated. Therefore, in this paper, we investigated the inhibitory effects of the biflavonoids using an in silico screening method. The docking results showed that the inhibitory effects of the biflavonoids on α-glucosidase from three different sources were different. Taiwaniaflavone-bacteria α-glucosidase complex (−9.37 kcal/mol), taiwaniaflavone-human α-glucosidase complex (−9.69 kcal/mol) and hinokiflavone-Saccharomyces cerevisiae α-glucosidase complex (−10.79 kcal/mol) had the lowest binding energies compared with the other biflavonoids, apigenin and acarbose. These compounds formed a considerable number of hydrogen bonds and hydrophobic interactions with active site residues of the various α-glucosidase, leading to structural changes and inhibition of enzyme activity. The online evaluation of absorption, distribution, metabolism, excretion and toxicity (ADMET) parameters proved that all biflavonoids had better pharmacokinetic properties and lower toxicity. This study suggested that hinokiflavone and taiwaniaflavone could be used as effective α-glucosidase inhibitors, which will help to develop more potent drugs to regulate the postprandial hyperglycemia. [ABSTRACT FROM AUTHOR]

Drying herbs is a crucial method for stabilizing and preserving their essential properties and bioactive compounds. Although freeze drying is the preferred method for most herbs, it is expensive due to high energy consumption and operating costs. Biflavonoids are dimeric flavonoids that have recently been recognized as potential molecules possessing biological activities, such as antiviral and antimicrobial activity, and as effective molecules for the treatment of neurodegenerative and metabolic diseases and for cancer therapies. In this study, we performed a comparative analysis of freeze drying, air drying and oven drying to evaluate their effects on biflavonoid content in yellow ginkgo leaves (Ginkgo biloba L.). After drying, we performed spectrophotometric analysis to determine the browning index, pigments, phenolic compounds and antioxidant activity, while HPLC-DAD was used for the identification and quantification of individual biflavones (amentoflavone, bilobetin, ginkgetin, isoginkgetin and sciadopitysin). The most abundant biflavonoids were isoginkgetin and bilobetin, the amounts of which exceeded 1000 µg/g dw in all leaf samples. They were followed by ginkgetin and sciadopitysin, the amounts of which were about 30% lower. The drying method did not influence biflavone content or the total carotenoids, total polyphenols and total flavonoids. Consequently, our study suggests that all three methods may be used for the preparation of yellow ginkgo leaves as a source of biflavones and other bioactive compounds. [ABSTRACT FROM AUTHOR]

Ten compounds, including three new bioflavonoids (1–3) and seven known compounds (4–10), were identified in the ethyl acetate fraction of the 85 % ethanol extract of Selaginella delicatula. The structures of the new compounds were determined through spectroscopic data analysis, and their absolute configurations were established using circular dichroism (CD). All the isolated compounds were tested for their antiproliferative effects on MCF‐7, HepG2, and HEK 293T cells. Compounds 1 and 5 exhibited significant cytotoxicity against MCF‐7 cells, effectively inhibiting their proliferation. Meanwhile, compounds 1, 2, 5, and 7 respectively exhibited strong inhibitory effects on HepG2 cells. Furthermore, when we combined the IC50 values of compounds 3, 5, and 7 on HEK 293T cells, we discovered that they selectively inhibited cell growth. [ABSTRACT FROM AUTHOR]

Dimeric flavonoids, also called biflavonoids, are bioactive compounds that exhibit various activities described in the literature, including antibacterial, antifungal, antiviral, anti-inflammatory, analgesic, antioxidant, vasorelaxant, and anticancer properties. This work focuses on the anticancer action of naturally occurring dimeric flavonoids against prostate and breast cancer, as well as on the mechanisms of action involved in their activity and presents the most current information on this subject in the literature. In the present review, we summarize the latest findings on the antiproliferative activity of 33 dimeric flavonoid-based compounds selected from recently published studies. The tests conducted were in silico and in vitro and demonstrated the cytotoxic activity potential of biflavonoids against prostate and breast tumor cells. Biflavonoids were capable of interfering with the migration and replication of cancer cells and their mechanism of action is related to cell death pathways, especially apoptosis, necrosis, and ferroptosis. These compounds decreased mitochondrial membrane potential and significantly increased intracellular levels of reactive oxygen species (ROS). Additionally, they significantly upregulated the expression of p21, Bax, and cleaved caspase-3, while downregulating Bcl-2 and caspase-3 levels, indicating their cell death mechanism of action is through the Bcl-2/Bax/cleaved caspase-3 pathway and cell cycle arrest. The biflavonoids here related have shown promising anticancer activity and are considered potential drug candidates for prostate and breast cancer treatment.

Garcinia livingstonei T. Anderson, also referred to as African or Lowveld mangosteen, is a medicinal plant belonging to the Clusiaceae family and is used in traditional medicine to treat variety of diseases including diabetes, parasitic infections, microbial infections, and other ailments. This review provides an overview of this medicinal plant by highlighting its traditional applications, phytochemical properties, pharmacological activities, and toxicity, in addition to offering guidance for future G. livingstonei studies. These bioactivities include antimicrobial, antioxidant, antiparasitic, antiviral, and antiproliferative activities. The findings of this work reveal that the pharmacological activities of G. livingstonei crude extracts and bioactive compounds confirm the diversified use, and the effectiveness of G. livingstonei leaves, stem, bark, and fruits in the traditional remedies of many diseases. To date, about 38 secondary metabolites have been isolated from the different parts of this plant, with xanthones and biflavonoids being particularly prominent. Pharmacological and chemical research suggests that G. livingstonei contains a variety of bioactive compounds, which is worthy of comprehensive and in-depth research. Nevertheless, animal toxicological examinations and efficacy studies are still required to conclusively validate the traditional uses and in vitro pharmacological activities. [Display omitted] • Garcinia livingstonei is used in traditionally to treat variety of diseases in South Africa and other African countries. • G. livingstonei has antioxidant, antimicrobial, antioxidant, antiparasitic, antiviral, and antiproliferative activities. • About 38 secondary metabolites have been isolated from the plant, with xanthones and biflavonoids being particularly prominent. • Further studies should focus on in vivo studies. [ABSTRACT FROM AUTHOR]

Genus Zamia is a diverse group of cycads belonging to the family Zamiaceae which includes most cycads. It is ranked as the second-largest genus of extant cycads in the new world. In contrast to other cycad species, Zamia species are trunkless, deciduous shrubs. The genus Zamia is by far the most ecologically varied, widely dispersed, and species-rich genus in the Americas. They are dioecious plants with male and female reproductive cones. Zamia plants are considered rich sources of numerous different natural metabolites, which may contribute to various biological activities such as cytotoxic, antimicrobial, antioxidant, and anti-inflammatory activities. These metabolites include flavonoids, biflavonoids, phenolic acids, volatile oils, and lignans that are considered the significant components of the phytochemical profile of Zamia. Zamia is a popular ornamental plant. It is also acknowledged as a therapeutic herb in both conventional and Western medicine. Various Zamia species have traditionally been used to treat a range of ailments by elderly locals in various locations. These ethnobotanical uses have led researchers to discover some valuable pharmacological properties of some Zamia species like cytotoxic, antiprotozoal, antioxidant, antimicrobial, and anti-Alzheimer activities. In this review, we have given an overview of different phytochemicals types present in Zamia species and their reported bioactivities in addition, the pharmacological, and ethnobotanical properties of certain Zamia species. [ABSTRACT FROM AUTHOR]

Garcinia madruno is rich in antioxidant biflavonoids that could be used to treat oxidative-related diseases. Up to now, its commercial application is challenging due to the poor water solubility of biflavonoids. This work aimed to develop a green and sustainable process to improve the solubility and dissolution rate of G. madruno biflavonoids by the development of 100% natural nanodispersions using peel extracts of this neotropical fruit. Three hydroalcoholic extracts were elaborated with different concentrations of biflavonoids and epicarp proportions. The biflavonoid natural suspensions were obtained by evaporating the ethanol of the different extracts. As a control, suspensions stabilized with commercial surfactants were compared to each other. Two natural nanosuspensions with different concentrations of biflavonoids and one nanosuspension stabilized with commercial surfactants were obtained. All dispersions had submicrometric particle distribution. M3-S nanosuspension (stabilized by commercial stabilizer) was the smallest dispersion with an average particle size of 256.6 nm, whereas natural suspension (NS-1 and NS 2) had better performance in the short-term stability and improved the solubility and dissolution rate until 400% in comparison of M3-S and isolate morelloflavone. Our results demonstrated that it was possible to formulate a biflavonoid suspension using their own plant compounds as natural stabilizers. [ABSTRACT FROM AUTHOR]

The bryophytes are the second largest group of land plants and are represented by three lineages: Marchantyophyta (liverworts), Anthocerotophyta (hornworts), and Bryophyta (mosses). They occupy a wide variety of habitats, from deserts to Antarctica, and exercise great ecological importance. These facts and their wide use in traditional medicine raise the question of what is known about moss chemistry. This paper gathered studies from the last 52 years about the compounds identified in mosses, aiming to address the following questions: Are mosses chemically under-studied? How many families, genera, and species of mosses have been chemically studied? Which continent and countries have been responsible for the majority of these studies? A literature search was performed in major scientific databases, using a combination of keywords. A total of 199 papers were compiled, of which 45% were published during the last decade. Only a small percentage of moss species has been studied, mostly from Europe and Asia. Dicranales and Hypnales are the most studied orders. In general, fatty acids and flavonoids are the most commonly reported classes of compounds. Biflavonoids and triflavonoids are detected mainly in derived clades of mosses, while coumarins are most reported for basal groups. Akthough only a small percentage of moss species has been chemically studied, most of these studies were published in the last decade—there has been a 135% increase in the number of reported compounds in the last 13 years. The emergence of new equipment, which can produce high-resolution spectra with small amounts of sample, combined with bioinformatics tools, has undoubtedly contributed to the increase of chemical investigation of mosses. Also, advances in the identification and phylogenetics of moss groups are contributing to a better understanding of them generally, which should lead also to increased study of moss chemistry. [ABSTRACT FROM AUTHOR]

Drying herbs is a crucial method for stabilizing and preserving their essential properties and bioactive compounds. Although freeze drying is the preferred method for most herbs, it is expensive due to high energy consumption and operating costs. Biflavonoids are dimeric flavonoids that have recently been recognized as potential molecules possessing biological activities, such as antiviral and antimicrobial activity, and as effective molecules for the treatment of neurodegenerative and metabolic diseases and for cancer therapies. In this study, we performed a comparative analysis of freeze drying, air drying and oven drying to evaluate their effects on biflavonoid content in yellow ginkgo leaves (Ginkgo biloba L.). After drying, we performed spectrophotometric analysis to determine the browning index, pigments, phenolic compounds and antioxidant activity, while HPLC-DAD was used for the identification and quantification of individual biflavones (amentoflavone, bilobetin, ginkgetin, isoginkgetin and sciadopitysin). The most abundant biflavonoids were isoginkgetin and bilobetin, the amounts of which exceeded 1000 µg/g dw in all leaf samples. They were followed by ginkgetin and sciadopitysin, the amounts of which were about 30% lower. The drying method did not influence biflavone content or the total carotenoids, total polyphenols and total flavonoids. Consequently, our study suggests that all three methods may be used for the preparation of yellow ginkgo leaves as a source of biflavones and other bioactive compounds.

This study aimed to isolate the flavone dimers in the acetone extract of Araucaria columnaris leaves and evaluate their potential biological activities. Three flavone dimers, 1-3, were isolated and identified by spectroscopic analysis using UV, IR, NMR, and mass spectrometry. The acetone extract and isolated metabolites were examined for their antiangiogenic activity against the Calf Pulmonary Arterial Endothelial (CPAE) cell and antioxidant performance using 2,2-diphenyl-1-picrylhydrazyl (DPPH). The results showed that 4',4'",7,7"-tetra-O-methylcupressuflavone (1) and acetone extract had IC50 values of 272.95±7.05 and 239.36±13.50 μg/mL, respectively, against CPAE cell. The other two isolated metabolites, 4',7,7"-tri-O-methylcupressuflavone (2) and 4"',7-di-O-methylcupressuflavone (3), showed high activity with IC50 values of 39.5±1.44 and 66.13±15.96 μg/mL, respectively. Although none of the individual components demonstrated any detectable antioxidant activity (IC50 > 100 μg/mL), the acetone extract showed moderate antioxidant activity with an IC50 value of 69.2 μg/mL. [ABSTRACT FROM AUTHOR]

Toxicodendron succedaneum (L.) Kuntze (Anacardiaceae) is a deciduous tree widely distributed in South and Southeast Asia. The resin of T. succedaneum is used in decorating traditional handicrafts, and resinous latex is poisonous. The plant yields a commercially important wax and treats asthma, cough, fever, ear infections, pulmonary infections, diarrhoea, dysentery, nose bleeding, and liver disorders. The scientific literature on T. succedaneum was collected from Scopus, PubMed, and Google Scholar. Major bioactive compounds reported in the plant are urushiols, bichalcones, biflavonoids such as succedaneaflavanone, agathisflavone, rhusflavanone, amentoflavone, cupressuflavone, robustaflavone, volkensiflavone, morelloflavone, and hinokiflavone. In-vitro studies have demonstrated the antioxidant, antibacterial, antitumor, and antileukemic activities of T. succedaneum, supporting the rationale behind its traditional use. Biflavonoids exhibited a strong antiviral effect by inhibiting the replication of HIV, HBV, and HSV. However, with the presence of hinokiflavone and a skin-irritating oil (urushiol), the plant causes severe allergies in humans, which urges to standardize the effectiveness of this species. The available literature on T. succedaneum suggests insufficient data on pharmacological studies in experimental animals. Much research needs to be done to confirm its folk medicinal uses for developing phytopharmaceutical drugs.

Despite the many strategies employed to slow the spread of cancer, the development of new anti-tumor drugs and the minimization of side effects have been major research hotspots in the anti-tumor field. Natural drugs are a huge treasure trove of drug development, and they have been widely used in the clinic as anti-tumor drugs. Selaginella species in the family Selaginellaceae are widely distributed worldwide, and they have been well-documented in clinical practice for the prevention and treatment of cancer. Biflavonoids are the main active ingredients in Selaginella, and they have good biological and anti-tumor activities, which warrant extensive research. The promise of biflavonoids from Selaginella (SFB) in the field of cancer therapy is being realized thanks to new research that offers insights into the multi-targeting therapeutic mechanisms and key signaling pathways. The pharmacological effects of SFB against various cancers in vitro and in vivo are reviewed in this review. In addition, the types and characteristics of biflavonoid structures are described in detail; we also provide a brief summary of the efforts to develop drug delivery systems or combinations to enhance the bioavailability of SFB monomers. In conclusion, SFB species have great potential to be developed as adjuvant or even primary therapeutic agents for cancer, with promising applications. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effect of biflavonoids in Ginkgo biloba leaves on tacrolimus metabolism. First, the inhibitory effects of five main biflavonoids (amentoflavone, sciadopitysin, ginkgetin, isoginkgetin, bilobetin) in G. biloba leaves on tacrolimus metabolism were investigated in vitro in human liver microsomes (HLM), and the concentration‐dependent inhibition was further calculated. Then the time‐dependent inhibition activities of five biflavonoids were studied and the drug interaction was studied in Sprague–Dawley (SD) rats. Finally, the molecular mechanism of inhibition was explored by molecular docking. The results of in vitro incubation in HLM showed tacrolimus metabolism was strongly inhibited by amentoflavone, ginkgetin, and bilobetin, whose IC50 value was 5.57, 3.16, and 5.03 μM, respectively. The time‐dependent inhibition of the three above biflavonoids at 50 μM was 33.47%–50.89%. In the in vivo study in rats, the AUC0−t and Cmax of tacrolimus increased 3.8‐fold and 2.5‐fold after oral preadministration with amentoflavone. The molecular docking results showed that the inhibitory effect may be related to the formation of hydrogen bonds. The results showed that long‐term combination of G. biloba leaves and tacrolimus may cause drug–drug interactions. This study provided theoretical and experimental basis for rational drug use in clinical practice. [ABSTRACT FROM AUTHOR]

Grape seed procyanidin extract (GSE) had been reported to exert antineoplastic properties in preclinical studies. A modified phase I, open-label, dose-escalation clinical study was conducted to evaluate the safety, tolerability, MTD, and potential chemopreventive effects of leucoselect phytosome (LP), a standardized GSE complexed with soy phospholipids to enhance bioavailability, in heavy active and former smokers. Eight subjects ages 46-68 years were enrolled into the study and treated with escalating oral doses of LP for 3 months. Bronchoscopies with bronchoalveolar lavage and bronchial biopsies were performed before and after 3 months of LP treatment. Hematoxylin and eosin stain for histopathology grading and IHC examination for Ki-67 proliferative labeling index (Ki-67 LI) were carried out on serially matched bronchial biopsy samples from each subject to determine responses to treatment. Two subjects were withdrawn due to issues unrelated to the study medication, and a total of 6 subjects completed the full study course. In general, 3 months of LP, reaching the highest dose per study protocol was well tolerated and no dosing adjustment was necessary. Such a treatment regimen significantly decreased bronchial Ki-67 LI by an average of 55% (P = 0.041), with concomitant decreases in serum miR-19a, -19b, and -106b, which were oncomirs previously reported to be downregulated by GSE, including LP, in preclinical studies. In spite of not reaching the original enrollment goal of 20, our findings nonetheless support the continued clinical translation of GSE as an antineoplastic and chemopreventive agent against lung cancer.

Neurological disorders are becoming more common, and there is an intense search for molecules that can help treat them. Several natural components, especially those from the flavonoid group, have shown promising results. Ginkgetin is the first known biflavonoid, a flavonoid dimer isolated from ginkgo (Ginkgo biloba L.). Later, its occurrence was discovered in more than 20 different plant species, most of which are known for their use in traditional medicine. Herein we have summarized the data on the neuroprotective potential of ginkgetin. There is evidence of protection against neuronal damage caused by ischemic strokes, neurotumors, Alzheimer's disease (AD), and Parkinson's disease (PD). Beneficial effects in ischemic strokes have been demonstrated in animal studies in which injection of ginkgetin before or after onset of the stoke showed protection from neuronal damage. AD protection has been the most studied to date. Possible mechanisms include inhibition of reactive oxygen species, inhibition of β-secretase, inhibition of Aβ fibril formation, amelioration of inflammation, and antimicrobial activity. Ginkgetin has also shown positive effects on the relief of PD symptoms in animal studies. Most of the available data are from in vitro or in vivo animal studies, where ginkgetin showed promising results, and further clinical studies should be conducted. [ABSTRACT FROM AUTHOR]

The pericarp of fruit can be differentiated into endocarp, mesocarp, and exocarp. To explore the differences in gene expression and metabolites in different tissues of the pericarp, the fruits of sumac (Toxicodendron vernicifluum) were separated into endocarp and mesocarp-exocarp. The metabolites and transcriptome of exocarp-mesocarp and endocarp of Toxicodendron vernicifluum were analyzed by HPLC–QTOF-MS/MS and RNA sequencing, respectively. A total of 52 phenolic compounds were identified, including 3 phenylpropane derivatives, 10 urushiol compounds and 39 flavonoids. The exocarp-mesocarp contained more urushiol compounds and flavonoid glycosides while the endocarp contained more biflavonoids, such as rhusflavone and dihydromorelloflavone. The characteristic component of endocarp was rhusflavone and the characteristic component of exocarp-mesocarp was urushiol (triene). Most of the genes involved in flavonoid synthesis pathway were upregulated in endocarp compared with exocarp-mesocarp and positively correlated with the content of flavonoids. The candidate genes related to the synthesis of components of flavonoid glycosides and biflavonoids were screened. Metabolomic and transcriptomic analyses provide new insights into the synthesis and distribution of flavonoid glycosides and biflavonoids in the fruits of Toxicodendron vernicifluum. • The characteristic component of sumac endocarp was rhusflavone. • The characteristic component of sumac exocarp-mesocarp was urushiol(triene). • Genes in flavonoid synthesis upregulated in endocarp compared with exocarp-mesocarp. [ABSTRACT FROM AUTHOR]

Biflavonoids are dimers of flavonoids created by a covalent connection of C-C or C-O-C between two flavonoids and have been found to have a variety of pharmacological effects, including the ability to treat diabetes mellitus (DM). In the current investigation, the inhibitory effect of biflavonoids extracted from Araucaria hunsteinii K. Schum towards the target protein α-glucosidase was assessed using a combination of in-vitro experiments and in-silico molecular docking approach. The biflavonoids' inhibition properties were contrasted with those of acarbose, a widely used pharmaceutical for treating type 2 DM. AutoDock Vina was employed to analyze the conformational sites and docking parameters, such as binding affinity and inhibition constant. In-silico studies showed that biflavonoids effectively interacted with the active site of the α-glucosidase enzyme, which is in charge of cleaving not only bonding of the α-1,4 but also the α-1,6 glycosidic on the exterior of amylose or amylopectin residues to obtain simple sugars. The docking experiments revealed that biflavonoids had tighter binding forces than acarbose against α-glucosidase. The selected biflavonoids, 7-O-methylcupressuflavone; 7,7"-di-O-methylagathisflavone, 4',4"'-di-O-methylamentoflavone and 4"',7-di-O-methylcupresuflavone showed an IC50 of 78.32±0.52; 388.39±0.68; 389.76±1.55 and 537.98±2,35 μM, respectively. These biflavonoids had a low binding affinity and more hydrogen bond interactions with the target enzyme, which had several important amino acid residues. The effectiveness of these compounds in inhibiting the enzyme may be explained by some of their hydrophobic interactions. Therefore, the study comes to the conclusion that biflavonoids are prospective antidiabetic agents and should be taken into consideration when developing candidates for new antidiabetic medicines. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the reservoir of natural products against the SARS-CoV-2 virus and to identify suitable candidates in order to recommend appropriate phytotherapy. Adequately prepared 65 molecules from traditional Chinese medicine with proven antiviral properties were subjected to docking analysis using AutoDock Vina 4 software with the aim to investigate binding affinity and interactions of compounds with Mpro from the SARS-CoV-2 virus. Biflavonoids and tannins show best docking scores with -9,80 kcal/mol for biflavonoids and -9,00 kcal/mol for tannins. Biflavonoids: amentoflavone, agathistaflavone, robustaflavone, hinokiflavone and rhusflavanone were tested for their radical scavenging activity. Partition coefficients were examined by RP-HPLC. Evaluation of drug-likeness properties of investigated biflavonoids suggested rhusflavanone as a molecule with the best ADMET characteristics. Anti-inflammatory activity of rhusflavanone was investigated in LPS stimulated RAW264.7 macrophages. Tested biflavonoids exibit beneficial effects against inflammation by scavenging free radicals and by suppressing the production of proinflammatory mediators by macrophages. Both predictions of affinity spectra for substances (PASS) and in vitro testing showed promising biological activity of investigated biflavonoids. A Quantum chemical study was performed in order to calculate the thermodynamic, molecular orbital, and electrostatic potential of selected molecules and to compare their biological and chemical features. Our results highlighted antioxidant, anti-inflammatory and antiviral properties of investigated compounds, emphasizing the significance of biflavonoid moiety to selected characteristics, which encourage further investigational strategies against COVID-19. [Display omitted] • Considering applications against COVID 19 biflavonoid products exhibit a best docking scores and binding affinities to main protease of SARS-CoV-2 virus among examined natural products with antiviral properties. • Amentoflavone, agathistflavone, robustaflavone, hinokiflavone and rhusflavanone show promising antioxidative and antiviral characteristics. • Rhusflavanone possess the best drug-likeness features among selected biflavonoids as well as anti-inflamatory and modulatory effects in LPS treated RAW264.7 cells. [ABSTRACT FROM AUTHOR]

Ginkgo (Ginkgo biloba L.) is one of the oldest trees on earth and its leaves are traditionally used as herbal medicine. The beneficial effects of ginkgo leaves are attributed to the presence of flavonoids and terpene trilactones. Monomeric flavonoids are frequently studied, but recently much attention has been paid to biflavonoids, dimeric flavonoids, due to their biological activity and potential pharmaceutical use. The development of a suitable and effective extraction protocol focusing on biflavonoids is increasingly in demand. Therefore, in this study, we developed an optimized extraction protocol using deep eutectic solvents (DESs) to extract flavonoids from ginkgo leaves, with special attention to biflavonoids. Initially, 250 DESs were screened using COSMOtherm software to identify those that could strongly solubilize biflavonoids and flavonoids, and the results obtained indicated 15 DESs. Among them, betaine: ethylene glycol (B:EG) 1:2 with 30 % H 2 O (w/w) showed higher extraction efficiency than the extraction performed with 80 % methanol. In a next step, the extraction with the selected DES was further optimized using a Box-Behnken experimental design. The results obtained showed that the optimum extraction conditions using the selected DES were as follows: Extraction time 45 minutes, the ratio of the initial mass of the shredded leaves to the volume of the DES 20:1 and the temperature 20 °C. Finally, the concentrations of the 5 most abundant biflavonoids in ginkgo leaves (amentoflavone, ginkgetin, isoginkgetin, bilobetin and sciadopitysin) in the extracts were determined using HPLC-DAD. The results showed that B:EG 1:2 with 20 % H 2 O (w/w) and 30 % H 2 O (w/w) were suitable for the extraction of all five biflavonoids. [Display omitted] • Developed an optimized extraction process for Ginkgo biflavonoids using deep eutectic solvents (DESs). • Screened 250 DESs, identifying 15 with potential as biflavonoid solvents. • B:EG 1:2 with 30 % water (w/w) demonstrated higher extraction efficiency than 80 % methanol. • Optimized extraction conditions set at 45 min, 20:1 leaf mass to DES volume ratio, at 20 °C • B:EG 1:2 with 20 % and 30 % water (w/w) proved effective for extracting all 5 biflavonoids. [ABSTRACT FROM AUTHOR]

In the early 20th century, the first dimeric flavonoid, ginkgetin, was isolated from the yellow leaves of the ginkgo (Ginkgo biloba L.) tree. Today, researchers have identified nearly 600 different forms of dimeric flavonoids or biflavonoids, though they have received considerably less attention than their monomeric counterparts. Ginkgo, where the first biflavonoid was discovered, serve as a rich source of various biflavonoids and represent a model organism for our project investigating the role of these compounds in plants. To date, we have developed a robust method for the simultaneous determination and quantification of the five most abundant biflavonoids- amentoflavone, bilobetin, ginkgetin, isoginkgetin and sciadopitysin. We have also conducted comprehensive profiling of these compounds across various tissues and throughout different growing stages. Our research suggests that the localization and increased accumulation of biflavonoids may be indicative of their roles within plants, a topic that will be discussed during the presentation. [ABSTRACT FROM AUTHOR]

Toxoplasmosis and cancer are serious worldwide diseases, and the available drugs cause serious side effects. Investigation for new alternative therapies from natural sources is now an increasing concern. Herein, we carried out, for the first time, an in vitro screening of Cycas rumphii Miq. leaves for toxoplasmocidal effect, using Viruluent RH Toxoplasma gondii, and cytotoxic activity against HEPG-2, HCT-116 and HELA cancer cell lines using MTT assay. Among the tested extracts, the ethyl acetate fraction was the most effective against T. gondii, with an EC50 of 3.51 ± 0.2 µg/mL compared to cotrimoxazole (4.18 ± 0.01 µg/mL) and was the most potent against the tested cell lines, especially HEPG-2, with an IC50 of 6.98 ± 0.5 µg/mL compared to doxorubicin (4.50 ± 0.2 µg/mL). Seven compounds were isolated from the ethyl acetate fraction by extensive chromatographic techniques and fully elucidated using different spectroscopies. Compound (7) is an undescribed 4′, 4′′′ biapigenin di-C-glucoside, which showed a strong cytotoxic activity. Four known biflavonoids (1, 2, 4 and 5) in addition to a phenolic acid ester (3) and a flavonoid glycoside (6) were also isolated. Compounds (1, 3 and 6) were reported for the first time from C. rumphii. [ABSTRACT FROM AUTHOR]

Toxicodendron succedaneum (L.) Kuntze (Anacardiaceae) is a deciduous tree widely distributed in South and Southeast Asia. The resin of T. succedaneum is used in decorating traditional handicrafts, and resinous latex is poisonous. The plant yields a commercially important wax and treats asthma, cough, fever, ear infections, pulmonary infections, diarrhoea, dysentery, nose bleeding, and liver disorders. The scientific literature on T. succedaneum was collected from Scopus, PubMed, and Google Scholar. Major bioactive compounds reported in the plant are urushiols, bichalcones, biflavonoids such as succedaneaflavanone, agathisflavone, rhusflavanone, amentoflavone, cupressuflavone, robustaflavone, volkensiflavone, morelloflavone, and hinokiflavone. In-vitro studies have demonstrated the antioxidant, antibacterial, antitumor, and antileukemic activities of T. succedaneum, supporting the rationale behind its traditional use. Biflavonoids exhibited a strong antiviral effect by inhibiting the replication of HIV, HBV, and HSV. However, with the presence of hinokiflavone and a skinirritating oil (urushiol), the plant causes severe allergies in humans, which urges to standardize the effectiveness of this species. The available literature on T. succedaneum suggests insufficient data on pharmacological studies in experimental animals. Much research needs to be done to confirm its folk medicinal uses for developing phytopharmaceutical drugs. [ABSTRACT FROM AUTHOR]

Pro-oxidants play a crucial role in cancer by causing oxidative stress that leads to apoptosis. The present study demonstrates the prooxidant and anti-inflammatory potential of ethyl acetate and methanolic extracts of Garcinia xanthochymus fruit. Oxidation of Trolox and NADH activity indicated the pro-oxidant capacity of the extracts. Significant decrease in cell viability in B16F10 and MDA-MB-231 cancer cell lines and significant increase in caspase 3 activity after treatment with extracts indicated pro-oxidant induced apoptosis. Pre-treatment with the extracts significantly inhibited ROS, reduced NO production, inhibited LPS-induced COX-2 and suppressed IL-6 and TNF-α expression. HRMS analysis showed the presence of compounds like biflavonoids, xanthones, phloroglucinols, benzophenones, etc. The fruit is rich in total phenolic and flavonoid contents, and have DPPH radical scavenging, ferric reducing antioxidant and metal chelating potential. This study report for the first time about the anticancer and anti-inflammatory properties of G. xanthochymus whole fruit.

The production of eukaryotic mRNAs requires transcription by RNA polymerase (pol) II and co-transcriptional processing, including capping, splicing, and cleavage and polyadenylation. Pol II can positively affect co-transcriptional processing through interaction of factors with its carboxyl terminal domain (CTD), comprising 52 repeats of the heptapeptide Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7, and pol II elongation rate can regulate splicing. Splicing, in turn, can also affect transcriptional activity and transcription elongation defects are caused by some splicing inhibitors. Multiple small molecule inhibitors of splicing are now available, some of which specifically target SF3B1, a U2 snRNP component. SF3B1 inhibition results in a general downregulation of transcription elongation, including premature termination of transcription caused by increased use of intronic poly(A) sites. Here, we have investigated the effect of Madrasin and Isoginkgetin, two non-SF3B1 splicing inhibitors, on splicing and transcription. Surprisingly, we found that both Madrasin and Isoginkgetin affect transcription before any effect on splicing, indicating that their effect on pre-mRNA splicing is likely to be indirect. Both small molecules promote a general downregulation of transcription. Based on these and other published results, we conclude that these two small molecules should not be considered as primarily pre-mRNA splicing inhibitors., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tellier et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Hinokiflavone (HF), classified as a flavonoid, is a main bioactive compound in Platycladus orientalis and Selaginella. HF exhibits activities including anti-HIV, anti-inflammatory, antiviral, antioxidant and anti-tumor effects. The study aimed to explore the function and the mechanisms of HF on acetaminophen (APAP)-induced acute liver injury. Results indicated that HF treatment mitigated the impact of APAP on viability and restored levels of MDA, GSH and SOD on HepG2 cells. The accumulation of reactive oxygen species (ROS) mitochondrial membrane potential (MMP) in HepG2 cells stimulated by APAP were also blocked by HF. HF reduced the levels of pro-apoptotic and pro-pyroptotic proteins. Flow cytometry analysis and fluorescence staining results were consistent with western blot analysis. Following HF treatment in the APAP-induced cell model, there was observed an augmentation in the phosphorylation of Stat3 and an increase in the expression of SIX4. However, not only silenced the SIX4 protein in HepG2 cells by siRNA, but also adding the Stat3 inhibitor (Stattic), attenuated the anti-apoptotic and anti-pyroptotic effects of HF significantly. Furthermore, HF alleviated liver damage in C57BL/6 mice model. Overall, our study demonstrated that HF mitigates apoptosis and pyroptosis induced by APAP in drug-induced liver injury (DILI) through the SIX4/Akt/Stat3 pathway in vivo and in vitro. HF may have promising potential for for the treatment of DILI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Agathisflavone is a flavonoid that exhibits anti-inflammatory and anti-oxidative properties. Here, we investigated the neuroprotective effects of agathisflavone on central nervous system (CNS) neurons and glia in the cerebellar slice ex vivo model of neonatal ischemia. Cerebellar slices from neonatal mice, in which glial fibrillary acidic protein (GFAP) and SOX10 drive expression of enhanced green fluorescent protein (EGFP), were used to identify astrocytes and oligodendrocytes, respectively. Agathisflavone (10 μM) was administered preventively for 60 min before inducing ischemia by oxygen and glucose deprivation (OGD) for 60 min and compared to controls maintained in normal oxygen and glucose (OGN). The density of SOX-10 + oligodendrocyte lineage cells and NG2 immunopositive oligodendrocyte progenitor cells (OPCs) were not altered in OGD, but it resulted in significant oligodendroglial cell atrophy marked by the retraction of their processes, and this was prevented by agathisflavone. OGD caused marked axonal demyelination, determined by myelin basic protein (MBP) and neurofilament (NF70) immunofluorescence, and this was blocked by agathisflavone preventative treatment. OGD also resulted in astrocyte reactivity, exhibited by increased GFAP-EGFP fluorescence and decreased expression of glutamate synthetase (GS), and this was prevented by agathisflavone pretreatment. In addition, agathisflavone protected Purkinje neurons from ischemic damage, assessed by calbindin (CB) immunofluorescence. The results demonstrate that agathisflavone protects neuronal and myelin integrity in ischemia, which is associated with the modulation of glial responses in the face of ischemic damage.

Abstract Background The arthropod-borne Mayaro virus (MAYV) causes “Mayaro fever,” a disease of medical significance, primarily affecting individuals in permanent contact with forested areas in tropical South America. Recently, MAYV has attracted attention due to its likely urbanization. There are currently no licensed drugs against most mosquito-transmitted viruses. Punica granatum (pomegranate) fruits cultivated in Brazil have been subjected to phytochemical investigation for the identification and isolation of antiviral compounds. In the present study, we explored the antiviral activity of pomegranate extracts in Vero cells infected with Mayaro virus. Methods The ethanol extract and punicalagin of pomegranate were extracted solely from the shell and purified by chromatographic fractionation, and were chemically identified using spectroscopic techniques. The cytotoxicity of the purified compounds was measured by the dye uptake assay, while their antiviral activity was evaluated by a virus yield inhibition assay. Results Pomegranate ethanol extract (CC50 = 588.9, IC50 = 12.3) and a fraction containing punicalagin as major compound (CC50 = 441.5, IC50 = 28.2) were shown to have antiviral activity (SI 49 and 16, respectively) against Mayaro virus, an alphavirus. Immunofluorescence analysis showed the virucidal effect of pomegranate extract, and transmission electron microscopy (TEM) revealed damage in viral particles treated with this extract. Conclusions The P. granatum extract is a promising source of antiviral compounds against the alphavirus MAYV and represents an excellent candidate for future studies with other enveloped RNA viruses. Graphical abstract

CHEMICAL COMPOSITION AND PHOTOPROTECTIVE AND ANTIRADICAL ACTIVITIES OF THE BRANCHES OF Platonia insignis (CLUSIACEAE). The chemical study of the branches of Platonia insignis enabled the isolation of the biflavonoid morelloflavone and the identification, by mass spectrometry, of over 9 polyphenols, including eight biflavonoids, one benzophenone, and one xanthone. The in vitro biological tests of solar photoprotection and antiradical activities against the crude extract and Hex and AcOEt fractions showed relevant results, which confirm the high pharmaceutical potential of the species.

The aim of this study was to identify bioactive secondary metabolites from Ochna rhizomatosa with potential inhibitory effects against HIV and Plasmodium falciparum. A phytochemical study of O. rhizomatosa root barks resulted in the identification of three new biflavonoids (1–3), along with four known ones (4–7). Compound 7 (Gerontoisoflavone A) was a single flavonoid present in the rootbark of the plant and was used as a reference. Compound 1 (IC50 = 0.047 µM) was the only one with a noteworthy inhibitory effect against HIV-1 integrase in vitro. Chicoric acid (IC50 = 0.006 µM), a pure competitive inhibitor of HIV-1 integrase, was used as control. Compound 2 exhibited the highest antiplasmodial activity (IC50 = 4.60 µM) against the chloroquine-sensitive strain of Plasmodium falciparum NF54. Computational molecular docking revealed that compounds 1 and 2 had the highest binding score (−121.8 and −131.88 Kcal/mol, respectively) in comparison to chicoric acid and Dolutegravir (−116 and −100 Kcal/mol, respectively), towards integrase receptor (PDB:3LPT). As far as Plasmodium-6 cysteine s48/45 domain inhibition is concerned, compounds 1 and 2 showed the highest binding scores in comparison to chloroquine, urging the analysis of these compounds in vivo for disease treatment. These results confirm the potential inhibitory effect of compounds 1 and 2 for HIV and malaria treatment. Therefore, our future investigation to find inhibitors of these receptors in vivo could be an effective strategy for developing new drugs. [ABSTRACT FROM AUTHOR]

Biflavonoids are C-C or C-O-C linked flavonoid dimers with highly restricted presence in plant species. They are extensively reported to possess interesting pharmacological properties. The chromatographic fractionation and purification of CH2Cl2/MeOH (1:1) extract of the root of Rhus ruspolli led to the isolation of a new biflavonoid (1) along with four other known biflavonoids (2-5). The structure of the compounds were identified based on the analysis of NMR spectroscopic and mass spectrometric data and also in comparison with reported literature data. Compounds 2-5 were assayed for their antioxidant activity using DPPH and displayed potent in vitro antioxidant activities. The percentage radical scavenging activities were 78.32, 68.90, 93.22 and 92.00 for compounds 2-5, respectively. The highest activity was observed for compound 4 and 5 with IC50 values of 7.90 and 8.40, respectively, which are even greater than that of ascorbic acid (IC50 9.90). The high antioxidant activity of the compounds could be due to the presence of free hydroxyl groups in the flavonoids. The antioxidant activities of these compounds support the traditional uses of the plant in treatment of wound, ectoparasite and as antibacteria and indicates the potential use of these compounds as drug lead candidates. [ABSTRACT FROM AUTHOR]

Three new biflavonoids, umcephabiovins C − E (1 − 3), along with fourteen known compounds were isolated from the twigs and leaves of Cephalotaxus oliveri. Their structures and configurations were elucidated by UV, IR, NMR, ECD, and HR-ESI-MS spectra. Compounds 1 − 3 exhibited significant α-glucosidase inhibitory activity with IC50 values of 7.05 ± 2.66, 24.45 ± 4.73, and 1.84 ± 1.14 μM, respectively. Compound 11 showed moderate cytotoxicity against the BaF3/T315I cell line. [ABSTRACT FROM AUTHOR]

Grape seed procyanidin extract (GSE) has been reported to exert antineoplastic properties via the inhibition of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) eicosanoid pathways. In addition, ample data link carcinogenesis to inflammatory events involving other major eicosanoid metabolic pathways, including prostacyclin (PGI2) and 15-hydroxyeicosatetraenoic acid (15-HETE). We therefore evaluated the effects of GSE on prostacyclin synthase (PTGIS)/PGI2 and 15-lipoxigenase-2 (15-LOX-2)/15-HETE productions by human lung premalignant and malignant cells and correlated the findings with antiproliferative or proapoptotic effects of GSE. The effects of GSE on PGI2 and 15-HETE productions by human bronchoalveolar lavage (BAL) cells ex vivo were also determined. We further evaluated the bioactivity of oral administration of leucoselect phytosome (a standardized GSE) in the lungs of subjects participating in a lung cancer chemoprevention trial, by comparing the antiproliferative effects of coculturing matched pre- versus posttreatment BAL fluids with lung premalignant and malignant cells. GSE significantly increased PGI2 (as measured by 6-keto PGF1α) and 15-HETE productions by these cells. Transfections of PTGIS or 15-LOX-2-specific siRNA partially abrogated the antiproliferative or proapoptotic effects of GSE in lung premalignant and malignant cells, respectively. GSE also increased PTGIS and inhibition of caspase-3, and transfection of 15-LOX-2 siRNA abrogated the GSE-induced apoptosis in A549 cells. In addition, culture supernatants from ex vivo GSE-treated baseline BAL cells, as well as BAL fluids from subjects treated with leucoselect phytosome, significantly decreased proliferations of lung premalignant and malignant cells. Our findings support the continued investigation of GSE as an anti-neoplastic and chemopreventive agent against lung cancer. Cancer Prev Res; 9(12); 925-32. ©2016 AACR.

Colorectal cancer (CRC) has the third highest incidence worldwide. Epidemiological studies showed that the consumption of fruit and vegetables containing procyanidins (PCA), polymers of flavan-3-ols, is associated with lower CRC risk. However, the molecular mechanisms supporting this positive association are unclear. This study investigated the capacity of PCA with different degrees of polymerization to reduce CRC cell growth, characterizing the underlying mechanisms. Compared to the monomer ((-)-epicatechin) and the trimer, the hexamer (Hex) was the most active at reducing CRC cell viability. Hex caused a concentration- (2.5-50 μM) and time- (24-72 h) dependent decrease in the viability of six human CRC cell lines in culture. Hex caused CRC apoptotic Caco-2 cell death within 24 h, as evidenced by caspase 3 and caspase 9 activation, DNA fragmentation, and changes in nuclear morphology/staining. Hex-induced apoptosis occurs through the mitochondrial pathway, as evidenced by an increased Bad mitochondrial translocation, and cytochrome c release from the mitochondria to the cytosol. Hex also arrested the Caco-2 cell cycle at G2 /M phase and upregulated genes involved in autophagy. Mechanistically, in Caco-2 cells Hex inhibited the PI3K/Akt signaling pathway, causing the downstream downregulation of proteins involved in the regulation of cell survival (Bad, GSK-3β). Accordingly, the Akt inhibitor MKK-2206 decreased Bad and GSK-3β phosphorylation. MKK-2206 decreased cell growth, having an additive effect with Hex. In conclusion, our results show that large PCA can inhibit CRC cell growth via the Akt kinase pathway, demonstrating a mechanism to explain the epidemiological evidence linking PCA-rich diets with lower CRC risk. © 2016 Wiley Periodicals, Inc.

Despite the many strategies employed to slow the spread of cancer, the development of new anti-tumor drugs and the minimization of side effects have been major research hotspots in the anti-tumor field. Natural drugs are a huge treasure trove of drug development, and they have been widely used in the clinic as anti-tumor drugs. Selaginella species in the family Selaginellaceae are widely distributed worldwide, and they have been well-documented in clinical practice for the prevention and treatment of cancer. Biflavonoids are the main active ingredients in Selaginella, and they have good biological and anti-tumor activities, which warrant extensive research. The promise of biflavonoids from Selaginella (SFB) in the field of cancer therapy is being realized thanks to new research that offers insights into the multi-targeting therapeutic mechanisms and key signaling pathways. The pharmacological effects of SFB against various cancers in vitro and in vivo are reviewed in this review. In addition, the types and characteristics of biflavonoid structures are described in detail; we also provide a brief summary of the efforts to develop drug delivery systems or combinations to enhance the bioavailability of SFB monomers. In conclusion, SFB species have great potential to be developed as adjuvant or even primary therapeutic agents for cancer, with promising applications.

Ginkgo (Ginkgo biloba L.) is one of the most distinctive plants, characterized by excellent resistance to various environmental conditions. It is used as an ornamental plant and is recognized as a medicinal plant in both traditional and Western medicine. Its bioactive potential is associated with the presence of flavonoids and terpene trilactones, but many other compounds may also have synergistic effects. Flavonoid dimers—biflavonoids—are important constituents of ginkgophytopharmaceuticals. Currently, the presence of 13 biflavonoids has been reported in ginkgo, of which amentoflavone, bilobetin, sciadopitysin, ginkgetin and isoginkgetin are the most common. Their role in plants remains unknown, but their bioactivity and potential role in the management of human health are better investigated. In this review, we have provided an overview of the chemistry, diversity and biological factors that influence the presence of biflavonoids in ginkgo, as well as their bioactive and health-related properties. We have focused on their antioxidant, anticancer, antiviral, antibacterial, antifungal and anti-inflammatory activities as well as their potential role in the treatment of cardiovascular, metabolic and neurodegenerative diseases. We also highlighted their potential toxicity and pointed out further research directions. [ABSTRACT FROM AUTHOR]

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A chalcone-flavonone type biflavonoid, trichocladabiflavone A (1), along with eight known biflavonoids (2–9) were isolated from the 70% EtOH extract of Selaginella trichoclada. Their structures were elucidated by extensive spectroscopic analyses. Compound 1 was the first chalcone-flavonone type biflavonoid reported in the genus Selaginella. Moreover, compound 1 exhibited moderate cytotoxicity against DU145, MCF-7 and PC3 human cancer cell lines. [ABSTRACT FROM AUTHOR]

A new biflavonoids, (2R,2''R)-7-O-methyl-2,3,2'',3''-tetrahydrorobustaflavone (1), along with five known flavonoids (2-6) were isolated from the MeOH extract of Aster tataricus. Among them, compounds 1-2 were the C-3'-C-6'' type biflavonoids obtained from the genus Aster for the first time. The structures and absolute configurations of compound 1 was confirmed based on extensive spectroscopic and circular dichroism analyses. Compound 1 exhibited moderate cytotoxicity against seven human cancer A549, HepG2, PC3, DU145, MCF-7, LOVO and NCI-H1975 cell lines. Compound 1 remarkably inhibited the proliferation of A549 cancer cells with IC50 value of 5.4 μM. Further preliminary pharmacological study, 1 induces A549 cell death by non-apoptotic forms through flow cytometry and cell scratch assay data. [ABSTRACT FROM AUTHOR]

Given the lack of adequate research on Dioon spinulosum (D. spinulosum) Dyer Ex Eichler, this study was conducted focusing on different biological activities and phytochemical investigation of D. spinulosum for the first time. D. spinulosum showed strong protective activity against DNA damage and potent activity against VERO cell line. It also presented antimicrobial and hepatoprotective activity. Phytochemical investigation of the leaves resulted in isolation of two new flavonoids, apigenin 7-O-α-d-glucopyranoside (15) and amentoflavone 7-O-α-l-rhamnopyranoside (16), in addition to fifteen known compounds: phytone (1), trans-phytol (2), β-sitosterol (3), stigmasterol (4), oliveriflavone (5), 7,4′,7″,4″′-tetramethylamentoflavone (6), 7,4',7''-trimethylamentoflavone (7), scaidopitysin (8), bilobetin (9), isoginkgetin (10), aromadendrin (11), sotusflavone (12), engeletin (14) and eriocitrin (17) for the first time together with amentoflavone (13). Compounds (11) and (13) displayed very strong cytotoxic activity and showed the highest protective activity against DNA damage. [ABSTRACT FROM AUTHOR]

Amentoflavone, robustaflavone, 2″,3″-dihydro-3′,3‴-biapigenin, 3′,3‴-binaringenin, and delicaflavone are five major hydrophobic components in the total biflavonoids extract from Selaginella doederleinii (TBESD) that display favorable anticancer properties. The purpose of this study was to develop a new oral delivery formulation to improve the solubilities, dissolution rates, and oral bioavailabilities of the main ingredients in TBESD by the solid dispersion technique. Solid dispersions of TBESD with various hydrophilic polymers were prepared, and different technologies were applied to select the suitable carrier and method. TBESD amorphous solid dispersion (TBESD-ASD) with polyvinylpyrrolidone K-30 was successfully prepared by the solvent evaporation method. The physicochemical properties of TBESD-ASD were investigated by scanning electron microscopy, differential scanning calorimetry, and Fourier-transform infrared spectroscopy. As a result, TBESD was found to be molecularly dispersed in the amorphous carrier. The solubilities and dissolution rates of all five ingredients in the TBESD-ASD were significantly increased (nearly 100% release), compared with raw TBESD. Meanwhile, TBESD-ASD showed good preservation stability for 3 months under accelerated conditions of 40 °C and 75% relative humidity. A subsequent pharmacokinetic study in rats revealed that Cmax and AUC0–t of all five components were significantly increased by the solid dispersion preparation. An in vivo study clearly revealed that compared to raw TBESD, a significant reduction in tumor size and microvascular density occurred after oral administration of TBESD-ASD to xenograft-bearing tumor mice. Collectively, the developed TBESD-ASD with the improved solubility, dissolution rates and oral bio-availabilities of the main ingredients could be a promising chemotherapeutic agent for cancer treatment.

Neurological disorders are becoming more common, and there is an intense search for molecules that can help treat them. Several natural components, especially those from the flavonoid group, have shown promising results. Ginkgetin is the first known biflavonoid, a flavonoid dimer isolated from ginkgo (Ginkgo biloba L.). Later, its occurrence was discovered in more than 20 different plant species, most of which are known for their use in traditional medicine. Herein we have summarized the data on the neuroprotective potential of ginkgetin. There is evidence of protection against neuronal damage caused by ischemic strokes, neurotumors, Alzheimer’s disease (AD), and Parkinson’s disease (PD). Beneficial effects in ischemic strokes have been demonstrated in animal studies in which injection of ginkgetin before or after onset of the stoke showed protection from neuronal damage. AD protection has been the most studied to date. Possible mechanisms include inhibition of reactive oxygen species, inhibition of β-secretase, inhibition of Aβ fibril formation, amelioration of inflammation, and antimicrobial activity. Ginkgetin has also shown positive effects on the relief of PD symptoms in animal studies. Most of the available data are from in vitro or in vivo animal studies, where ginkgetin showed promising results, and further clinical studies should be conducted.

Lotus rhizome is an important aquatic vegetable, but the blackening of lotus rhizome epidermis (LRE) seriously affects its appearance and quality, which makes lotus rhizome products unmarketable. In this study, the effects of polyphenols and iron on the LRE color were studied to explore the possible mechanism of LRE blackening. Results indicated that the measurable total phenols contents in the mud treatment (MT) group were significantly reduced, and the total iron contents were significantly increased compared with the bruised treatment group (p < 0.05). The high-performance liquid chromatography results showed that the main polyphenols in LRE were dopa, gallocatechin, and catechin, as well as a small amount of catechol, epicatechin, proanthocyanidin B2, and proanthocyanidin C1. Moreover, the results of color difference and ultraviolet adsorption spectroscopy showed that there were obviously black or brown-gray of dopa (525 nm), gallocatechin (504.5 nm), and catechin (550 and 504.5 nm) with FeCl 2 . The simulated system treatment of LRE further confirmed that the chromaticity effect of dopa and iron in bruised LRE was similar to that of the MT group, whereas 1% (w/w) ascorbic acid, 2% (w/w) EDTA-2Na, or 3% (w/w) citric acid could solely prohibit the blackening. This suggested that the dopa in LRE and FeCl 2 in mud may mainly combine into [2(DOPA-2H + )+Fe 3+ ] - through non-covalent interaction, which leads to the blackening of bruised LRE under neutral conditions. These results can guide the storage of lotus rhizomes and improve the development of the lotus rhizome industry., (© 2024 Institute of Food Technologists.)

Background: The arthropod-borne Mayaro virus (MAYV) causes "Mayaro fever," a disease of medical significance, primarily affecting individuals in permanent contact with forested areas in tropical South America. Recently, MAYV has attracted attention due to its likely urbanization. There are currently no licensed drugs against most mosquito-transmitted viruses. Punica granatum (pomegranate) fruits cultivated in Brazil have been subjected to phytochemical investigation for the identification and isolation of antiviral compounds. In the present study, we explored the antiviral activity of pomegranate extracts in Vero cells infected with Mayaro virus. Methods: The ethanol extract and punicalagin of pomegranate were extracted solely from the shell and purified by chromatographic fractionation, and were chemically identified using spectroscopic techniques. The cytotoxicity of the purified compounds was measured by the dye uptake assay, while their antiviral activity was evaluated by a virus yield inhibition assay. Results: Pomegranate ethanol extract (CC50 = 588.9, IC50 = 12.3) and a fraction containing punicalagin as major compound (CC50 = 441.5, IC50 = 28.2) were shown to have antiviral activity (SI 49 and 16, respectively) against Mayaro virus, an alphavirus. Immunofluorescence analysis showed the virucidal effect of pomegranate extract, and transmission electron microscopy (TEM) revealed damage in viral particles treated with this extract. Conclusions: The P. granatum extract is a promising source of antiviral compounds against the alphavirus MAYV and represents an excellent candidate for future studies with other enveloped RNA viruses. [ABSTRACT FROM AUTHOR]

Constitutively active BCR-ABL kinase fusions are causative mutations in the pathogenesis of hematopoietic neoplasias including chronic myelogenous leukemia (CML). Although these fusions have been successfully targeted with kinase inhibitors, drug-resistance and relapse continue to limit long-term survival, highlighting the need for continued innovative drug discovery. We developed a time-resolved Förster resonance energy transfer (TR-FRET) -based assay to identify compounds that disrupt stimulation of the ABL kinase by blocking its ability to bind the positive regulator RIN1. This assay was used in a high throughput screen (HTS) of two small molecule libraries totaling 444,743 compounds. 708 confirmed hits were counter-screened to eliminate off-target inhibitors and reanalyzed to prioritize compounds with IC50 values below 10 μM. The CML cell line K562 was then used to identify five compounds that decrease MAPK1/3 phosphorylation, which we determined to be an indicator of RIN1-dependent ABL signaling. One of these compounds is a thiadiazole, and the other four are structurally related acyl piperidine amides. Notably, these five compounds lower cellular BCR-ABL1 kinase activity by blocking a positive regulatory interaction rather than directly inhibiting ABL catalytic function.