Search Results (60)

The capitula of Chrysanthemum indicum Linné or C. morifolium Ramatuelle (Kikuka in Japanese) are included in several formulae of Kampo medicines (traditional Japanese medicines), such as Chotosan, which is used for headache and dizziness. Luteolin, the principal constituent of C. indicum, has antioxidant and anti-inflammatory activities. However, the effects of other flavonoids on this crude drug have not yet been thoroughly investigated. To evaluate and compare anti-inflammatory effects, we used primary cultured rat hepatocytes, which produce proinflammatory mediators, such as nitric oxide (NO) and proinflammatory cytokines, in response to interleukin (IL)-1β. Eight derivatives of 5,7-dihydroxyflavone were purified and identified in the ethyl acetate-soluble fraction of a C. indicum capitulum extract: luteolin (Compound 1), apigenin (2), diosmetin (3), 5,7-dihydroxy-3′,4′,5′-trimethoxyflavone (4), acacetin (5), eupatilin (6), jaceosidin (7), and 6-methoxytricin (8). Luteolin is the most abundant compound in this fraction. All compounds significantly suppressed NO production in hepatocytes, with apigenin and acacetin showing the greatest efficacy. The comparison of the IC₅₀ values of the inhibition of NO production suggests that substitutions by hydroxyl and methoxy groups at the C-3′ and C-4′ positions of 5,7-dihydroxyflavone may be at least essential for the suppression of NO production. In hepatocytes, acacetin and luteolin decreased the levels of mRNAs encoding inducible nitric oxide synthase (iNOS), proinflammatory cytokines, including tumor necrosis factor, IL-6, and type 1 IL-1 receptor, which regulates inflammatory responses. Based on the comparison of the IC₅₀ values and the content, luteolin, jaceosidin, and diosmetin may be responsible for the anti-inflammatory effects of C. indicum capitula. Full article

Biflavonoids are a unique subclass of dietary polyphenolic compounds known for their diverse bioactivities. Despite these benefits, these biflavonoids remain largely underexplored due to their limited natural availability and harsh conditions required for their synthesis, which restricts broader research and application in functional foods and nutraceuticals. To address this gap, we synthesized a library of rare biflavonoids using a radical–nucleophile coupling reaction previously reported by our group. The food grade coupling reaction under weakly alkaline water at room temperature led to isolation of 28 heterocoupled biflavones from 11 monomers, namely 3′,4′-dihydroxyflavone, 5,3′,4′-trihydroxyflavone, 6,3′,4′-trihydroxyflavone, 7,3′,4′-trihydroxyflavone, diosmetin, chrysin, acacetin, genistein, biochanin A, and wogonin. The structures of the dimers are characterized by nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectroscopy (HRMS). In addition, we evaluated the antioxidant potential of these biflavones using a DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay and the DPPH value ranges between 0.75 to 1.82 mM of Trolox/mM of sample across the 28 synthesized dimers. Additionally, a three-dimensional quantitative structure–activity relationship (3D-QSAR) analysis was conducted to identify structural features associated with enhanced antioxidant activity. The partial least squares (PLS) regression QSAR model showed acceptable r² = 0.936 and q² = 0.869. Additionally, the average local ionization energy (ALIE), electrostatic potential (ESP), Fukui index (F-), and electron density (ED) were determined to identify the key structural moiety that was capable of donating electrons to neutralize reactive oxygen species. Full article

In this study, three new 3,7-dihydroxyflavone (1) derivatives with different sugars were designed and synthesised by click chemistry. Click chemistry requires the previously modification of building blocks with azide and alkyne groups and therefore, the 3,7-dihydroxyflavone (1) was first converted in 3,7-(prop-2-yn-yloxy)flavone (2) and acetobromo-α-D-glucose (3) was converted into 2,3,4,6-tetra-O-acetyl-β-glucopyranosyl azide (4). Subsequently, a click reaction was performed via copper-catalysed cycloaddition (CuAAC) between 2 and 4, as well as between 2 and 2-acetamido-3,4,6-tetra-O-acetyl-2-deoxy-β-D-glucopyranosyl (AG931) and, 2 and commercial 2-azidoethyl 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl (AG358), resulting in three distinct disubstituted flavone glycosides (5a–5c). Biological assays performed on L929 fibroblast cell lines and human glioblastoma astrocytoma U-251 cell lines indicated cytocompatibility with fibroblasts and reduced metabolic activity of GBM cells in the presence of compound 5b and 5c. To enhance therapeutic effect, improve local drug delivery, and overcome solubility issues of these high molecular weight compounds, the synthesised compounds were encapsulated in polymeric particles (polymersomes, PMs) composed of polylactic acid-polyethylene glycol (PEG-PLA) functionalized, once more by click chemistry, with 0.1 mol% transferrin mimetic (T7—HRPYIAH) peptide. The PMs were prepared by solvent displacement and exhibited stability over 100 days, encapsulation efficiency of 39–93%, and mean size diameters of 120–180 nm. The toxicity assays of the PMs on the U-251 cell line showed a significant decrease in metabolic activity, supporting the potential of this delivery system against GBM. Among the PMs tested, the flavone 5c-based PM demonstrated the highest efficacy. Full article

Aggressive behavior is regulated by intricate neural circuits and molecular mechanisms, notably through the interaction of brain-derived neurotrophic factor (BDNF) with its receptor, tropomyosin receptor kinase B (TrkB), which influences neuroplasticity and related behavioral phenotypes. We investigate the role of the BDNF signaling pathway in fish aggression using juvenile black rockfish (Sebastes schlegelii), which exhibit distinct aggressive phenotypes. The TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) was administered intraperitoneally at doses of 1.25, 2.5, and 5 mg/kg to assess its effects on the behavioral characteristics of high-aggression (H-agg) and low-aggression (L-agg) phenotypes. Our findings indicate the following: (1) The effects of 7,8-DHF are dose-dependent, with 2.5 mg/kg identified as the effective threshold dose for H-agg individuals; (2) in the H-agg group, this dose significantly reduced locomotor acceleration, angular velocity, and activity frequency, while prolonging the first movement latency; (3) in the L-agg group, only angular velocity was significantly decreased with the 2.5 mg/kg treatment, with no significant changes observed in other behavioral parameters. This study provides the first evidence for differential behavioral responses to 7,8-DHF in S. schlegelii, demonstrating dose-dependent aggression suppression in H-agg phenotypes and threshold-specific responses in L-agg phenotypes. These insights into the neuro-molecular basis of fish aggression can guide phenotype-specific management in aquaculture, potentially improving stress management, reducing injuries and mortality, and boosting productivity. Full article

Background/Objectives: Flavonoids are common ubiquitous components of plants and are consumed by humans and livestock in their diets. Many different activities have been proposed for a variety of flavonoids that play a role in the benefits of a plant-rich diet. On the downside, excessive exposure to some flavonoids comes with a risk of endocrine disruption. Our objective was to define the structural elements of flavones and selected other flavonoids required for endocrine-disrupting activities on each of four steroid receptors, estrogen, androgen, progesterone, and glucocorticoid receptors. Methods: This work presents a systematic screen for the hormone agonist or antagonist activity of a selected panel of flavonoids on estrogen, androgen, progesterone, and glucocorticoid receptors. The screen is focused on the positional requirements of hydroxyl substituents on the flavone backbone. Results: Each receptor exhibited a distinct pattern for structural requirements of the flavones to impact receptor signaling. The most active flavones exhibited antagonist activity on androgen and progesterone receptors with an IC₅₀ of 0.5 and 2 µM, respectively. Flavones only exhibited weak antagonism on glucocorticoid receptors. When active, flavones acted as estrogen receptor agonists. The findings were utilized to design and synthesize a novel flavone, 3-fluoro, 6,4′-dihydroxyflavone 14, that displays increased potency as an estrogen agonist (EC₅₀~30 nM). Modeling of the binding of this novel flavone predicts increased preference for ERα versus ERβ relative to the estrogenic phytoestrogen, genistein. Conclusions: The structural requirements for flavones to act as estrogen agonists and antagonists of other steroid receptors are defined. The synthesis of a novel flavone offers potential for topical applications where systemic estrogen activity is undesired. However, the results highlight the potential for endocrine disruption when certain flavones are consumed in quantity as supplements. Full article

Background: Gentamicin (GM) is extensively used as an antibiotic for the treatment of infections caused by Gram-negative bacteria. Oxidative stress and proinflammatory cytokines are implicated in GM-induced renal damage. Chrysin (CH), also known as 5,7-dihydroxyflavone, has been used in traditional medicine to treat various kidney disorders. The aim of this study was to investigate the antioxidant, anti-apoptotic, and anti-inflammatory effects of CH against nephrotoxicity induced by GM. Methods: Male rats were separated into four equal groups: a negative control group (NC), a CH-treated group (100 mg/kg/day per os), a group treated with GM (100 mg/kg/day IM), and a group treated with both GM and CH (100 mg/kg/day), for 10 days. Blood and urine renal markers were investigated. Results: GM caused increases in the serum creatinine and urea levels and decreases in creatinine clearance, urine flow, and urine volume in the GM-treated rats. Moreover, there were increases in the levels of IL-1β, TNF-α, IL-18, and MDA in the renal tissues, with an augmented expression of NF-κB/KIM-1, as well as decreases in antioxidant marker (GSH, GPx, CAT, and SOD) activities and decreased expressions of the anti-inflammatory transcription factors Nrf2 and AKT. The simultaneous treatment with CH in the GM-treated group protected renal tissues against the nephrotoxicity induced by GM, as demonstrated by the normalization of renal markers and improvement in histopathological damage. Conclusions: This study reveals that CH may attenuate GM-induced renal toxicity in rats. Full article

Background: It seems that some substances of plant origin may exert health-promoting activities in diabetes and its complications, including those concerning bones. Chrysin (5,7-dihydroxyflavone), present in honey, some plants, and food of plant origin, has been reported to exert, among others, antioxidative, anti-inflammatory and antidiabetic effects. The aim of this study was to investigate the effects of chrysin on the skeletal system of rats with experimental type 1 diabetes (T1D). Methods: The experiments were carried out on mature male Wistar rats. T1D was induced by a single streptozotocin injection. Administration of chrysin (50 or 100 mg/kg p.o., once daily) began two weeks later and lasted four weeks. Serum bone turnover markers, bone mass, density and mineralization, mechanical properties and histomorphometric parameters of cancellous and compact bone were examined. Results: T1D profoundly affected bone metabolism, leading to worsening of bone strength in comparison with the healthy controls. After administration of chrysin, slight improvement of only some parameters was demonstrated in relation to the diabetic controls. Conclusions: Results of the present study indicate that chrysin may exert some very limited favorable effects on the skeletal system in diabetic conditions. Full article

5,6-dihydroxyflavone (5,6-DHF), a flavonoid that possesses potential anti-inflammatory and antioxidant activities owing to its special catechol motif on the A ring. However, its function and mechanism of action against inflammation and cellular oxidative stress have not been elucidated. In the current study, 5,6-DHF was observed inhibiting lipopolysaccharide (LPS)-induced nitric oxide (NO) and cytoplasmic reactive oxygen species (ROS) production with the IC₅₀ of 11.55 ± 0.64 μM and 0.8310 ± 0.633 μM in murine macrophages, respectively. Meanwhile, 5,6-DHF suppressed the overexpression of pro-inflammatory mediators such as proteins and cytokines and eradicated the accumulation of mitochondrial ROS (mtROS). The blockage of the activation of cell surface toll-like receptor 4 (TLR4), impediment of the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 from the mitogen-activated protein kinases (MAPK) pathway, Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) from the JAK-STAT pathway, and p65 from nuclear factor-κB (NF-κB) pathways were involved in the process of 5,6-DHF suppressing inflammation. Furthermore, 5,6-DHF acted as a cellular ROS scavenger and heme-oxygenase 1 (HO-1) inducer in relieving cellular oxidative stress. Importantly, 5,6-DHF exerted more potent anti-inflammatory activity than its close structural relatives, such as baicalein and chrysin. Overall, our findings pave the road for further research on 5,6-DHF in animal models. Full article

Staphylococcus aureus, particularly drug-resistant strains, poses significant challenges in healthcare due to its ability to form biofilms, which confer increased resistance to antibiotics and immune responses. Building on previous knowledge that several flavonoids exhibit antibiofilm activity, this study sought to identify a novel flavonoid capable of effectively inhibiting biofilm formation and virulence factor production in S. aureus strains including MRSA. Among the 19 flavonoid-like compounds tested, 3,2′-dihydroxyflavone (3,2′-DHF) was identified for the first time as inhibiting biofilm formation and virulence factors in S. aureus with an MIC 75 µg/mL. The antibiofilm activity was further confirmed by microscopic methods. Notably, 3,2′-DHF at 5 µg/mL was effective in inhibiting both mono- and polymicrobial biofilms involving S. aureus and Candida albicans, a common co-pathogen. 3,2′-DHF reduces hemolytic activity, slime production, and the expression of key virulence factors such as hemolysin gene hla and nuclease gene nuc1 in S. aureus. These findings highlight the potential of 3,2′-DHF as a novel antibiofilm and antivirulence agent against both bacterial and fungal biofilms, offering a promising alternative to traditional antibiotics in the treatment of biofilm-associated infections. Full article

Naodesheng Tablet (Naodesheng Pian), a traditional Chinese medicine formula for stroke treatment, is made up of five herbal medicines, i.e., Sanqi, Gegen, Honghua, Shanzha, and Chuanxiong. However, the current Pharmacopoeia quality-marker (Q-marker) system cannot detect possible adulteration. Our study tried to use a new strategy, i.e., standards-library-dependent ultra-high-performance liquid chromatography-quadrupole-Orbitrap mass spectrometry (UHPLC-Q-Orbitrap MS/MS) putative identification, to reconstruct the Q-marker system. Through the strategy, 30 isomers were successfully differentiated (such as 2′-hydroxygenistein, luteolin, and kaempferol; ginsenoside Rg2 and ginsenoside Rg3; ginsenoside Rf and ginsenoside Rg1). In particular, 11 compounds were unexpectedly found in Naodesheng, including 2′-hydroxygenistein, 7,4′-dihydroxyflavone, pectolinarigenin, 7-methoxy-4′-hydroxyisoflavone, scoparone, matrine, 3,3′,4′,5,6,7,8-heptamethoxyflavone, 5-hydroxyflavone, diosgenin, chloesteryl acetate, and (+)-4-cholesten-3-one. In total, 68 compounds were putatively identified and fully elucidated for their MS spectra. Subsequently, relevant compounds were further investigated using UV-vis scanning experiments, semi-quantitative analysis, and quantum chemical calculation. Finally, five adulterated Naodesheng Tablets were used for validation experiments. The experiment successfully detected five adulterated ones via a lower-version LC-MS analysis. On this basis, three new candidates (hydroxy safflor yellow A (HSYA), citric acid, and levistilide A), along with puerarin and notoginsenoside R1, are re-nominated as the Q-markers for LC-MS analysis. The LC-MS analysis of puerarin, notoginsenoside R1, HSYA, citric acid, and levistilide A can clearly detect adulteration regarding all five herbal medicines mentioned above. Therefore, the reconstructed Q-markers are described as a “perfect” quality control system to detect adulteration in Naodesheng and will offer a valuable recommendation for the Pharmacopoeia Commission. Full article

Skin cancers are a dominant type of cancer that impacts millions per year. Cancer is a heterogeneous disease triggered by the irreversible impairment of cellular homeostasis and function. In this study, we investigated the activity of 37 structurally diverse flavonoids to find potentially active substances using two melanoma cell lines: C32 and A375. First, the cytotoxic potential and DNA biosynthesis inhibition of flavonoids were tested to determine the most active compounds in cancer and normal cells. Second, the molecular mechanism of the anticancer activity of flavonoids was elucidated using Western blot and immunofluorescence analyses. Compounds 1, 6, 15, and 37 reduced the viability of A375 and C32 cell lines via the intrinsic and extrinsic pathways of apoptosis, whereas 16 and 17 acted in a higher degree via the inhibition of DNA biosynthesis. In our experiment, we demonstrated the anticancer activity of compound 15 (5,6-dihydroxyflavone) for the first time. The in vitro studies pointed out the importance of the flavonoid core in hydroxyl groups in the search for potential drugs for amelanotic melanoma. Full article

The thrip (Megalurothrips usitatus) damages the flowers and pods of the cowpea, causing “black-heads and black-tails” (BHBT) symptoms and negatively affecting its economic value. However, the mechanism by which BHBT symptoms develop is still unknown. Our results showed that the microstructure of the pod epidermis was altered and the content of the plant’s resistance-related compounds increased after a thrip infestation. However, the contents of protein and free amino acids did not change significantly, suggesting that the nutritional value was not altered. Pathogens were found not to be involved in the formation of BHBT symptoms, as fungi and pathogenic bacteria were not enriched in damaged pods. Two herbivory-induced flavonoids—7,4′-dihydroxyflavone and coumestrol—were found to exert insecticidal activity. Our study clarified that BHBT symptoms are directly caused by the thrip. Thresholds for pest control need to be reconsidered as thrip herbivory did not degrade cowpea nutrition. Full article

This study was designed to evaluate the effects of different doses of the fibrous roots of Polygonatum cyrtonema Hua on the growth performance, slaughter parameters, meat quality, immune function, cytokines, antioxidant capacity, and intestinal morphology of white-feathered broilers. Also, the mechanism to improve immune functions of broilers was explored through network pharmacology and molecular docking technology. A total of 360 AA-white-feathered broilers were randomly divided into six groups (not separated by sex), with six repetitions per group (n = 10). The groups were as follows: basal diet (CON group), basal diet supplemented with 300 mg/kg aureomycin (ANT group), basal diet supplemented with 2%, 3%, and 4% fibrous root raw powder (LD, MD, and HD group), or basal diet supplemented with 3% fibrous root processed powder (PR group), in a 42-day experiment. The dietary inclusion of P. cyrtonema fibrous roots increased slaughter performance (p < 0.05), reduced the fat rate (p < 0.05), improved intestinal morphology (p < 0.05), and improved the immune organ index to varying degrees. It also significantly improved pH reduction, drip loss, and pressure loss of breast muscle and leg muscle (p < 0.05). Furthermore, it significantly improved immune and antioxidant functions including decreased MDA content of serum (p < 0.01), increased GSH-Px content (p < 0.01), IgG, IgA, and C4 contents (p < 0.05), and increased expression of IL-2 and IFN-γ (p < 0.01). Additionally, the mechanism by which fibrous roots improve immune function in broilers was explored using network pharmacology and molecular docking technology. Network pharmacology and molecular docking revealed that flavonoids such as baicalein, 4′,5-Dihydroxyflavone, 5,7-dihydroxy-6,8-dimethyl-3-(4′-hydroxybenzyl)-chroman-4-one, and 5,7-dihydroxy-3-(2′-hydroxy-4′-methoxybenzyl)-6,8-dimethyl-chroman-4-one were key components that enhanced immune function through the MAPK1 and other key targets involved in regulating the MAPK signaling pathway. From the findings, it can be concluded that incorporating P. cyrtonema Hua fibrous root as a natural feed supplement and growth promoter in broiler diets had a positive impact on bird health and performance. Full article

Freezing stress is the main factor affecting the normal growth and distribution of plants. The safe overwintering of a perennial deciduous plant is a crucial link to ensuring its survival and yield. However, little is known about the molecular mechanism of its gene regulation metabolites as related to its freeze-tolerance. In order to enhance our comprehension of freeze-tolerance metabolites and gene expression in dormant apple trees, we examined the metabolic and transcriptomic differences between ‘Ralls’ and ‘Fuji’, two apple varieties with varying degrees of resistance to freezing. The results of the freezing treatment showed that ‘Ralls’ had stronger freeze-tolerance than ‘Fuji’. We identified 302, 334, and 267 up-regulated differentially accumulated metabolites (DAMs) and 408, 387, and 497 down-regulated DAMs between ‘Ralls’ and ‘Fuji’ under −10, −15, and −20 °C treatment, respectively. A total of 359 shared metabolites were obtained in the upward trend modules, of which 62 metabolites were associated with 89 pathways. The number of up-regulated genes accounted for 50.2%, 45.6%, and 43.2% of the total number of differentially expressed genes (DEGs), respectively, at −10, −15, and −20 °C. Through combined transcriptome and metabolome analysis, we identified 12 pathways that included 16 DAMs and 65 DEGs. Meanwhile, we found that 20 DEGs were identified in the phenylpropanoid biosynthesis pathway and its related pathways, involving the metabolism of p-Coumaroyl-CoA, 7, 4′-Dihydroxyflavone, and scolymoside. These discoveries advance our comprehension of the molecular mechanism underlying apple freeze-tolerance and provide genetic material for breeding apple cultivars with enhanced freeze-tolerance. Full article

It was recently reported that the hydroxyflavones quercetin and kaempferol bind the orphan nuclear receptor 4A1 (NR4A1, Nur77) and act as antagonists in cancer cells and tumors, and they inhibit pro-oncogenic NR4A1-regulated genes and pathways. In this study, we investigated the interactions of flavone, six hydroxyflavones, seven dihydroxyflavones, three trihydroxyflavones, two tetrahydroxyflavones, and one pentahydroxyflavone with the ligand-binding domain (LBD) of NR4A1 using direct-binding fluorescence and an isothermal titration calorimetry (ITC) assays. Flavone and the hydroxyflavones bound NR4A1, and their K_D values ranged from 0.36 µM for 3,5,7-trihydroxyflavone (galangin) to 45.8 µM for 3′-hydroxyflavone. K_D values determined using ITC and K_D values for most (15/20) of the hydroxyflavones were decreased compared to those obtained using the fluorescence assay. The results of binding, transactivation and receptor–ligand modeling assays showed that K_D values, transactivation data and docking scores for these compounds are highly variable with respect to the number and position of the hydroxyl groups on the flavone backbone structure, suggesting that hydroxyflavones are selective NR4A1 modulators. Nevertheless, the data show that hydroxyflavone-based neutraceuticals are NR4A1 ligands and that some of these compounds can now be repurposed and used to target sub-populations of patients that overexpress NR4A1. Full article