Prenylated Flavonoids Research Articles

Discovery of Kuraridin as a Potential Natural Anti-Melanogenic Agent: Focusing on Specific Target Genes and Multidirectional Signaling Pathways.

Abnormal melanogenesis upon UV exposure causes excessive oxidative stress, leading to hyperpigmentation disorders. As a key rate-limiting enzyme in melanogenesis, tyrosinase is considered a primary target for depigmenting agents. Sophora flavescens is used as a food and in traditional medicine as a valuable source of prenylated flavonoids. The present study aimed to elucidate the anti-melanogenic effect and potential mechanism of kuraridin, one of the major prenylated flavonoids. Kuraridin showed anti-tyrosinase activity with an IC50 value in the nanomolar range, superior to that of kojic acid, a positive control. It significantly reduced tyrosinase activity with the least cytotoxicity, suppressing melanogenesis in α-MSH-induced B16F10 cells. Furthermore, kuraridin considerably reduced melanogenesis in a 3D human skin model. To elucidate the anti-melanogenic mechanism of kuraridin, target genes (KIT, MAP2K1, and PRKCA) and pathways (c-KIT and ETB-R pathways) were identified using network pharmacology. KIT and MAP2K1 are simultaneously involved in the c-KIT cascade and are considered the most important in melanogenesis. PRKCA acts directly on MITF and its downstream enzymes through another pathway. Docking simulation showed strong interactions between kuraridin and c-KIT, ERK1/2, and PKC encoded by target genes. Overall, the present study showed kuraridin to be a novel natural anti-melanogenic agent in hyperpigmentation disorders.

Six new prenylated flavonoids from Dodonaea viscosa with anti-Zika virus activity

Six new prenylated flavonoids, named visconaeas A-F (1–6), and eleven known isopentenyl flavonoids (7–17) were isolated from Dodonaea viscosa (L.) Jacq. The structures of the separated compounds were determined through comprehensive spectral analysis and quantum chemical calculations. These compounds were tested for their anti-Zika virus and cytotoxicity activities. The results indicated that compound 4 showed low cytotoxicity and strong anti-Zika virus potential with EC50 16.34 μM.

Biotransformation of Xanthohumol by Entomopathogenic Filamentous Fungi.

Xanthohumol (1) is a major prenylated flavonoid in hops (Humulus lupulus L.) which exhibits a broad spectrum of health-promoting and therapeutic activities, including anti-inflammatory, antioxidant, antimicrobial, and anticancer effects. However, due to its lipophilic nature, it is poorly soluble in water and barely absorbed from the gastrointestinal tract, which greatly limits its therapeutic potential. One method of increasing the solubility of active compounds is their conjugation to polar molecules, such as sugars. Sugar moiety introduced into the flavonoid molecule significantly increases polarity, which results in better water solubility and often leads to greater bioavailability. Entomopathogenic fungi are well known for their ability to catalyze O-glycosylation reactions. Therefore, we investigated the ability of selected entomopathogenic filamentous fungi to biotransform xanthohumol (1). As a result of the experiments, one aglycone (2) and five glycosides (3-7) were obtained. The obtained (2″E)-4″-hydroxyxanthohumol 4'-O-β-D-(4‴-O-methyl)-glucopyranoside (5) has never been described in the literature so far. Interestingly, in addition to the expected glycosylation reactions, the tested fungi also catalyzed chalcone-flavanone cyclization reactions, which demonstrates chalcone isomerase-like activity, an enzyme typically found in plants. All these findings undoubtedly indicate that entomopathogenic filamentous fungi are still an underexploited pool of novel enzymes.

Therapeutic potential of bark extracts from Macaranga denticulata on renal fibrosis in streptozotocin-induced diabetic rats

ABSTRACT Macaranga denticulata (MD) bark is commonly utilized in traditional medicine for diabetes prevention and treatment. The bark extract of MD is rich in prenyl or farnesyl flavonoids and stilbenes, which possess antioxidant properties. Although data suggest the potential therapeutic benefits of the use of MD in treating diabetic nephropathy (DN), the precise mechanisms underlying MD-initiated protective effects against DN are not well understood. This study aimed to assess the renoprotective properties of MD extract by examining renofibrosis inhibition, oxidative stress, and inflammation utilizing streptozotocin-induced DN male Sprague – Dawley rats. Diabetic rats were intraperitoneally injected with streptozotocin (STZ) to induce diabetes. After 6 days, these rats were orally administered MD extract (200 mg/kg/day) or metformin (200 mg/kg/day) for 14 days. The administration of MD extract significantly lowered blood glucose levels, restored body weight, and reduced urine levels of various biomarkers associated with kidney functions. Histopathological analysis revealed protective effects in both kidneys and pancreas. Further, MD extract significantly restored abnormalities in advanced glycation end products, oxidative stress biomarkers, and proinflammatory cytokine levels in STZ-treated rats. MD extract markedly reduced renal fibrosis biomarker levels, indicating recovery from renal injury, and reversed dysregulation of sirtuins and claudin-1 in the kidneys of rats with STZ-induced diabetes. In conclusion, data demonstrated the renoprotective role of MD extract, indicating plant extract’s ability to suppress oxidative stress and regulate proinflammatory pathways during pathological changes in diabetic nephropathy.

Prenylated Flavonoids in Sophora flavescens: A Systematic Review of Their Phytochemistry and Pharmacology.

Sophora flavescens has been widely used in traditional Chinese medicine for over 1700 years. This plant is known for its heat-clearing, damp-drying, insecticidal, and diuretic properties. Phytochemical research has identified prenylated flavonoids as a unique class of bioactive compounds in S. flavescens. Recent pharmacological studies reveal that the prenylated flavonoids from S. flavescens (PFS) exhibit potent antitumor, anti-inflammatory, and glycolipid metabolism-regulating activities, offering significant therapeutic benefits for various diseases. However, the pharmacokinetics and toxicological profiles of PFS have not been systematically studied. Despite the diverse biological effects of prenylated flavonoid compounds against similar diseases, their structure-activity relationship is not yet fully understood. This review aims to summarize the latest findings regarding the chemical composition, drug metabolism, pharmacological properties, toxicity, and structure-activity relationship of prenylated flavonoids from S. flavescens. It seeks to highlight their potential for clinical use and suggest directions for future related studies.

Flavonoids From the Aerial Parts of Sophora tonkinensis and Their Potential Anti-Inflammatory Activities.

Four undescribed prenylated flavonoids, sophoratones A-D (1-4), and 17 known flavonoids, were obtained from the aerial parts of Sophora tonkinensis. Their structures with absolute configurations were elucidated by detailed interpretation of NMR spectroscopy, mass spectrometry, and ECD calculations. Meanwhile, the ability of these compounds to inhibit the release of nitric oxide (NO) by a lipopolysaccharide induced mouse in RAW 264.7 cells was assayed. The results indicated that some compounds exhibited clear inhibitory effects, with IC50 ranging from 19.91±1.08 to 35.72±2.92 μM. These results suggest that prenylated flavonoids from the aerial parts of S. tonkinensis could potentially be used as a latent source of anti-inflammatory agents.

Prenylated Flavonoids of the Moraceae Family: A Comprehensive Review of Their Biological Activities.

Prenylated flavonoids (PFs) are natural flavonoids with a prenylated side chain attached to the flavonoid skeleton. They have great potential for biological activities such as anti-diabetic, anti-cancer, antimicrobial, antioxidant, anti-inflammatory, enzyme inhibition, and anti-Alzheimer's effects. Medicinal chemists have recently paid increasing attention to PFs, which have become vital for developing new therapeutic agents. PFs have quickly developed through isolation and semi- or full synthesis, proving their high value in medicinal chemistry research. This review comprehensively summarizes the research progress of PFs, including natural PFs from the Moraceae family and their pharmacological activities. This information provides a basis for the selective design and optimization of multifunctional PF derivatives to treat multifactorial diseases.

Wighteone, a prenylated flavonoid from licorice, inhibits growth of SW480 colorectal cancer cells by allosteric inhibition of Akt

Ethnopharmacological relevanceLicorice is a frequently used herbal medicine worldwide, and is used to treat cough, hepatitis, cancer and influenza in clinical practice of traditional Chinese medicine. Modern pharmacological studies indicate that prenylated flavonoids play an important role in the anti-tumor activity of licorice, especially the tumors in stomach, lung, colon and liver. Wighteone is one of the main prenylated flavonoids in licorice, and its possible effect and target against colorectal cancer have not been investigated. Aim of the studyThis study aimed to investigate the anti-colorectal cancer effect and underlying mechanism of wighteone. Materials and methodsSW480 human colorectal cancer cells were used to evaluate the in vitro anti-colorectal cancer activity and Akt regulation effect of wighteone by flow cytometry, phosphoproteomic and Western blot analysis. Surface plasmon resonance (SPR) assay, molecular docking and dynamics simulation, and kinase activity assay were used to investigate the direct interaction between wighteone and Akt. A nude mouse xenograft model with SW480 cells was used to verify the in vivo anti-colorectal cancer activity of wighteone. ResultsWighteone inhibited phosphorylation of Akt and its downstream kinases in SW480 cells, which led to a reduction in cell viability. Wighteone had direct interaction with both PH and kinase domains of Akt, which locked Akt in a “closed” conformation with allosteric inhibition, and Gln79, Tyr272, Arg273 and Lys297 played the most critical role due to their hydrogen bond and hydrophobic interactions with wighteone. Based on Akt overexpression or activation in SW480 cells, further mechanistic studies suggested that wighteone-induced Akt inhibition led to cycle arrest, apoptosis and autophagic death of SW480 cells. Moreover, wighteone exerted in vivo anti-colorectal cancer effect and Akt inhibition activity in the nude mouse xenograft model. ConclusionWighteone could inhibit growth of SW480 cells through allosteric inhibition of Akt, which led to cell cycle arrest, apoptosis and autophagic death. The results contributed to understanding of the anti-tumor mechanism of licorice, and also provided a rationale to design novel Akt allosteric inhibitors for the treatment of colorectal cancer.

Prenylated Flavanone Isolated from Dalea Species as a Potential Multitarget-Neuroprotector in an In Vitro Alzheimer's Disease Mice Model.

Alzheimer's disease (AD) involves a neurodegenerative process that has not yet been prevented, reversed, or stopped. Continuing with the search for natural pharmacological treatments, flavonoids are a family of compounds with proven neuroprotective effects and multi-targeting behavior. The American genus Dalea L. (Fabaceae) is an important source of bioactive flavonoids. In this opportunity, we tested the neuroprotective potential of three prenylated flavanones isolated from Dalea species in a new in vitro pre-clinical AD model previously developed by us. Our approach consisted in exposing neural cells to conditioned media (3xTg-AD ACM) from neurotoxic astrocytes derived from hippocampi and cortices of old 3xTg-AD mice, mimicking a local neurodegenerative microenvironment. Flavanone 1 and 3 showed a neuroprotective effect against 3xTg-AD ACM, being 1 more active than 3. The structural requirements to afford neuroprotective activity in this model are a 5'-dimethylallyl and 4'-hydroxy at the B ring. In order to search the mechanistic performance of the most active flavanone, we focus on the flavonoid-mediated regulation of GSK-3β-mediated tau phosphorylation previously reported. Flavanone 1 treatment decreased the rise of hyperphosphorylated tau protein neuronal levels induced after 3xTg-AD ACM exposure and inhibited the activity of GSK-3β. Finally, direct exposure of these neurotoxic 3xTg-AD astrocytes to flavanone 1 resulted in toxicity to these cells and reduced the neurotoxicity of 3xTg-AD ACM as well. Our results allow us to present compound 1 as a natural prenylated flavanone that could be used as a precursor to development and design of future drug therapies for AD.

Xanthohumol, a prenylated flavonoid from hops (Humulus lupulus L.) exerts multidirectional pro-healing properties towards damaged zebrafish hair cells by regulating the innate immune response

Xanthohumol (XN) is a prominent prenylated flavonoid present in the hop plant (Humulus lupulus L.). Despite undoubted pro-healing properties of hop plant, there is still a need for clinical investigations confirming these effects as well as the underlying molecular mechanisms. The present study was designed to (1) establish the role of XN in non-invasive inflammation induced by chemical damage to zebrafish hair cells, (2) clarify if it influences cell injury severity, neutrophil migration, macrophage activation, cell regeneration, and (3) find out whether it modulates the gene expression profile of chosen immune and stress response markers. All experiments were performed on 3 dpf zebrafish larvae. After fertilization the embryos were transferred to appropriate XN solutions (0.1 μM, 0.3 μM and 0.5 μM). The 40 min 10 μM CuSO4 exposure evoked severe damage to posterior lateral line hair cells triggering a robust acute inflammatory response. Four readouts were selected as the indicators of XN role in the process of inflammation: 1) hair cell death, 2) neutrophil migration towards damaged hair cells, 3) macrophage activation and recruitment to damaged hair cells, 4) hair cell regeneration. The assessments involved in vivo confocal microscopy imaging and qPCR based molecular analysis. It was demonstrated that XN (1) influences death pathway of damaged hair cells by redirecting their severe necrotic phenotype into apoptotic one, (2) impacts the immune response via regulating neutrophil migration, macrophage recruitment and activation (3) modulates gene expression of immune system markers and (4) accelerates hair cell regeneration.

Chemistry, bioactivities, structure-activity relationship, biosynthesis and metabolism of prenylated flavonoids in Moraceae plants.

Plants from Moraceae are globally popular as they represent a valuable resource with wide applications in food, health-care products, and other fields. Prenylated flavonoids are important active components in Moraceae. These compounds share a flavonoid skeleton with prenylated side chain, mostly in the form of single or multiple isoprenyl substituents and benzodimethylfuran structures. So far, nearly 400 prenylated flavonoids have been found in Moraceae, especially a large number of Diels-Alder adducts, which are characteristic components of this family. Due to their distinctive structures, diverse pharmacological properties and interesting synthesis processes, these compounds have attracted considerable attention from scientists. Herein, we review the advances in the structural characteristics, bioactivities, structure-activity relationships, biosynthesis strategies and in vivo metabolism of prenylated flavonoids in Moraceae plants, aiming at strengthening research efforts and utilization toward the great untapped potential of these unique constituents in human health.

Prenylated chromones and flavonoids isolated from the roots of Flemingia macrophylla and their anti-lung cancer activity

BackgroundThe successful launch of icaritin, a therapeutic drug for liver cancer derived from Epimedium brevicornu, has provided new impetus for the development of prenylated flavonoids in the field of oncology. Flemingia macrophylla is reported to contain characteristic prenylated flavonoids which can regulate the p53 protein. We aimed to isolate these constituents and conduct activity evaluation, structure–activity relationship, and mechanism studies to provide candidate compounds for antitumor drug development.MethodsIn this study, chromatographic techniques combined with spectroscopic methods were used to separate, purify, and identify the constituents of Flemingia macrophylla methanol extract. The cytotoxic activity of the constituents was evaluated using an MTT assay with A549 and H1975 cells as the model. The binding mechanism between the compounds and the p53 protein was investigated with molecular docking and validated with cellular thermal shift assay (CETSA). Western blotting (WB) was employed to detect the expression of p53 protein and apoptosis-related proteins in cells.ResultsChiral HPLC separation of racemates 1 and 7 provided two pairs of undescribed enantiomers (1a/1b and 7a/7b), along with eight known compounds (2 − 9) isolated from Flemingia macrophylla roots. Their structures were elucidated by spectroscopic analysis, and the absolute configurations of the enantiomers were determined from experimental and calculated electronic circular dichroism data. Compounds 1 − 7, and the non-prenyl analogues 10 − 13, were evaluated for cytotoxic activity against the human lung cancer A549 and H1975 cell line. Compounds 5 − 7 displayed better cytotoxicity than the positive control icaritin in A549 and H1975, with IC50 values ranging from 4.50 to 19.83 μmol·L-1 and < 5 μmol·L-1, respectively. The structure–activity relationships of the chromone or flavonoid analogues against A549 cells were discussed. Molecular docking results demonstrated that compound 7a has strong interaction with p53 and WB indicated that 7a induced apoptosis by increasing the p53 protein, decreasing the anti-apoptotic protein Bcl-2, and activating the caspase family in A549 cells. These results suggest that prenylated flavonoids are potential p53 protein activators.ConclusionThis study demonstrates that Flemingia macrophylla is rich in prenylated flavonoid constituents, among which compounds 5 and 7 exhibited significant cytotoxic activity against A549 cells and served as reference candidates for the design and development of prenylated compounds as antitumor therapeutic drugs.Graphical

Prenylated flavonoids isolated from the twigs of Artocarpus champeden as potential activators for tobacco powdery mildew and their mode of actions

BackgroundGolovinomyces cichoracearum (DC.) is the main pathogen for tobacco powdery mildew fungus disease. Its outbreaks often result in severe harvest losses for the yield and quality of tobacco. Artocarpus champeden is rich in prenylated flavonoids, which are important for the plant’s defensive strategies. With the aim of continuously exploring bioactive natural metabolites for agricultural chemicals, the chemical investigations on the twigs of A. champeden were carried out.ResultsSix new (1–6) and five known (7–11) prenylated flavonoids were isolated. Compound 1 is the first example of flavone whose prenylated side-chain is converted into an unusual 1H-pyrrol-2-yl functional group. Compounds 2 and 3 are rare flavones bearing a 4-methylfuran-2-yl moiety. The frameworks of the above three flavones are reported in natural products for the first time. Interestingly, compound 1 showed high anti-G. cichoracearum activity with an inhibition rate of 88.3% ± 6.2. This rate is higher than that of the positive control (with an inhibition rate of 81.5% ± 6.3) compared to the negative control, compounds 2–11 also showed potential activities with inhibition rates in the range of 50.9%–72.0%. In addition, the mechanistic studies on 1 revealed that it has a potent direct effect on conidiospores of G. cichoracearum and induces systemic acquired resistance for tobacco plants, which may be the reasons for its significant effects against G. cichoracearum.ConclusionsPowdery mildew is a fungal disease harmful to tobacco. Flavonoids have been identified as the sources of promising antifungal agents. For prenylated flavonoids, the combination of a flavonoid skeleton with prenylated side-chain can give the resultant more potential for biological activities. The successful isolation and structure identification of the above prenylated flavonoids provide new materials for the screening of powdery mildew inhibitors, and also contribute to the improved utilization of A. champeden.Graphical

Prenylated flavonoids from Dalea genus as xanthine oxidase inhibitors: In vitro bioactivity evaluation and molecular docking studies

Prenylated flavanones are a family of compounds with an important biological potential. Previously, anti-tyrosinase activity, acetylcholinesterase inhibitory activity, and neuroprotective effects of several prenyl flavanones isolated from different American Dalea genus species were reported. The biological potency of these kinds of compounds, together with the particularity of their chemical structures, encouraged us to investigate them for in vitro and in silico anti-xanthine oxidase activity. So, five prenyl-flavanones obtained from different Dalea sp (Dalea elegans, Dalea boliviana, and Dalea pazensis) were studied and the relationships between the structure of these prenyl-flavanones and their inhibitory activity were evaluated. Molecular docking studies were performed in order to propose the binding mode of the most active natural compound. 2′,4′-dihydroxy-5′-(1‴,1‴-dimethylallyl)-8-prenylpinocembrin (1) was the most active in this series showing an IC50 of 0.26 ± 0.07 µM comparable with the reference inhibitor, allopurinol. The presence of 5,7,2′,4′-tetrahydroxy substitution, accompanied by a prenyl group at 8-position in the A-ring, and a 5′ (1‴,1‴-dimethylallyl) were important to present a xanthine oxidase inhibitory activity. This fact was confirmed with molecular docking studies showing relevant interactions of 1 with the residues of the catalytic site of xanthine oxidase, and a binding energy of −7.3297 kcal mol−1. These results contributed not only to understanding the binding mode but also to validating the in vitro results. The obtained findings lead us to propose these prenyl-flavanones as lead compounds for the design and development of novel xanthine oxidase inhibitors for the treatment of diseases in which this enzyme is involved.

Stepwise Targeted Matching Strategy for Comprehensive Profiling of Xanthohumol Metabolites In Vivo and In Vitro Using UHPLC-Q-Exactive Orbitrap Mass Spectrometer.

Xanthohumol (XN), a natural prenylated flavonoid extracted and isolated from the hop plant (Humulus lupulus), possesses diverse pharmacological activities. Although the metabolites of XN have been investigated in the previous study, a comprehensive metabolic profile has been insufficient in vivo or in vitro until now. The current study was aimed at systematically elucidating the metabolic pathways of XN after oral administration to rats. Herein, a UHPLC-Q-Exactive Orbitrap MS was adopted for the potential metabolites detection. A stepwise targeted matching strategy for the overall identification of XN metabolites was proposed. A metabolic net (53 metabolites included) on XN in vivo and in vitro, as well as the metabolic profile investigation, were designed, preferably characterizing XN metabolites in rat plasma, urine, liver, liver microsomes, and feces. On the basis of a stepwise targeted matching strategy, the net showed that major in vivo metabolic pathways of XN in rats include glucuronidation, sulfation, methylation, demethylation, hydrogenation, dehydrogenation, hydroxylation, and so on. The proposed metabolic pathways in this research will provide essential data for further pharmaceutical studies of prenylated flavonoids and lay the foundation for further toxicity and safety studies.

Phytoestrogens and Amenorrhea in Athletes

Plants contain several different families of natural products. Phytoestrogens are one such compound that is found in variety of plant foods. On the basis of the chemical structure, phytoestrogens are classified into four major categories such as flavonoids, isoflavonoids, lignans, and stilbenes. Structurally phytoestrogens are very much similar to 17 β-estradiol, so they have a tendency to exhibit estrogen-like activity, which has increased the interest of researchers to use it as a hormone replacement therapy. Nowadays, special attention is given to various isoflavonoids including genistein, diadzens, coumestrol, equol, and several prenylated flavonoids mainly, 8-prenylnaringein and stilbene resveratrol. Menstrual changes and bone density may be favorably influenced by phytoestrogens. These compounds have not only been observed to mimic the role of estrogen in humans but have also shown to exhibit effects and action in both similar and divergent manner as of the hormone. The eventual action of phytoestrogen in specific cells is determined by several factors such as the relative levels of estrogen receptors both α and β and the varied number and types of coactivators and corepressors presently existing in the cell. An increase in the consumption of herbal and natural nutritional supplements with ergogenic goals with particular regard to ecdysteroids, phytosterols, and vegetal sterols has been observed in past among the athletes which call for the need to assess the knowledge of athletes and physically active individuals about the plant-based nutritional supplements as well as its associations with amenorrhea in female athletes, their health profile, and reproductive life.

Inhibitory Mechanism of Prenylated Flavonoids Isolated from Mulberry Leaves on α-Glucosidase by Multi-Spectroscopy and Molecular Dynamics Simulation.

Flavonoids have always been considered as the chemical basis for the hypoglycemic effect of mulberry leaves. In the course of our search for hypoglycemic effect agents from natural sources, a systematic study was launched to explore prenylated flavonoids from mulberry leaves. Herein, chemical investigation led to the isolation of 10 characteristic prenylated flavonoids, including two new compounds (1 and 3). Their structures were elucidated based on spectroscopic data. All compounds exhibited good α-glucosidase inhibitory activity in vitro, among which compound 2 had the best activity (IC50 = 2.6 μM), better than acarbose (IC50 = 19.6 μM). Additional in vivo tests have further demonstrated compound that compound 2 has a good ability to reduce postprandial blood glucose. Then, multi-spectroscopic methods and molecular simulation studies were used to study the inhibition mechanism. The results showed that compound 2 was a mixed inhibition of α-glucosidase and the binding process was spontaneous, with van der Waals forces as the main driving force, followed by hydrogen bonding and electrostatic forces. The above studies enriched the chemical basis of mulberry leaves, and the application of computational chemistry also provided a reference for future research on such structures.

Phytochemistry and pharmacology of natural prenylated flavonoids.

Prenylated flavonoids are a special kind of flavonoid derivative possessing one or more prenyl groups in the parent nucleus of the flavonoid. The presence of the prenyl side chain enriched the structural diversity of flavonoids and increased their bioactivity and bioavailability. Prenylated flavonoids show a wide range of biological activities, such as anti-cancer, anti-inflammatory, neuroprotective, anti-diabetic, anti-obesity, cardioprotective effects, and anti-osteoclastogenic activities. In recent years, many compounds with significant activity have been discovered with the continuous excavation of the medicinal value of prenylated flavonoids, and have attracted the extensive attention of pharmacologists. This review summarizes recent progress on research into natural active prenylated flavonoids to promote new discoveries of their medicinal value.

The multifaceted roles of R2R3 transcription factor HlMYB7 in the regulation of flavonoid and bitter acids biosynthesis, development and biotic stress tolerance in hop (Humulus lupulus L.)

Hop (Humulus lupulus) biosynthesizes the highly economically valuable secondary metabolites, which include flavonoids, bitter acids, polyphenols and essential oils. These compounds have important pharmacological properties and are widely implicated in the brewing industry owing to bittering flavor, floral aroma and preservative activity. Our previous studies documented that ternary MYB-bHLH-WD40 (MBW) and binary WRKY1-WD40 (WW) protein complexes transcriptionally regulate the accumulation of bitter acid (BA) and prenylflavonoids (PF). In the present study, we investigated the regulatory functions of the R2R3-MYB repressor HlMYB7 transcription factor, which contains a conserved N-terminal domain along with the repressive motif EAR, in regulating the PF- and BA-biosynthetic pathway and their accumulation in hop. Constitutive expression of HlMYB7 resulted in transcriptional repression of structural genes involved in the terminal steps of biosynthesis of PF and BA, as well as stunted growth, delayed flowering, and reduced tolerance to viroid infection in hop. Furthermore, yeast two-hybrid and transient reporter assays revealed that HlMYB7 targets both PF and BA pathway genes and suppresses MBW and WW protein complexes. Heterologous expression of HlMYB7 leads to down-regulation of structural genes of flavonoid pathway in Arabidopsis thaliana, including a decrease in anthocyanin content in Nicotiana tabacum. The combined results from functional and transcriptomic analyses highlight the important role of HlMYB7 in fine-tuning and balancing the accumulation of secondary metabolites at the transcriptional level, thus offer a plausible target for metabolic engineering in hop.

Prenylated Flavonoids of Genus Epimedium: Phytochemistry, Estimation and Synthesis

AbstractPrenylated flavonoids are the chemotaxonomic markers of genus Epimedium. Icariin, epimedin A, B and C are the main bioactive principles found in Epimedium spp. The chemical and pharmacological studies of a good number of prenylated flavonoids isolated from Epimedium species are reported in literature but their biosynthetic pathways have been explored to a limited extent only and remained ambiguous for a long time. In this review, an in‐depth and extensive coverage of Epimedium prenylated flavonoids is reported from 2012 to 2022 using SciFinder database for literature retreival. The review covers occurrence, synthesis, biosynthesis and quantification of prenylated flavonoids of genus Epimedium.