Flavonoid Compounds Research Articles

Caenorhabditis elegans as an Outstanding Model to Explore Flavonoids Under Stress Conditions

Abstract: Plants produce promising chemicals called secondary metabolites in response to stress, which protect against oxidative damage in both plants and humans. Reactive oxygen species (ROS) levels combined with an imbalance in the antioxidant responses can trigger oxidative stress that is related to many conditions such as Alzheimer's disease, diabetes, and cancer. One way to counteract or avoid the stress excess is by flavonoid administration, a class of plant metabolites with a consistent antioxidant action and the ability to inactivate the free radical excess. The mechanisms, as well as the benefits and toxicity of antioxidant products, can be tested in alternative animal models. The mechanisms, as well as the benefits and toxicity of antioxidant products, can be tested in alternative animal models. In this review, we explored how Caenorhabditis elegans, a nematode with high genetic similarity to human genes and the antioxidant response pathway conserved, can be considered an attractive model organism for testing flavonoid compounds. Here, we emphasize the crucial results regarding C. elegans and the flavonoid quercetin, focusing on oxidative stress and aging investigations. Also, this review highlights the quercetin benefits in C. elegans lifespan, healthspan, neurodegeneration, and impacts on insulin/IGF-1 signaling (IIS).

Isoliquiritigenin alleviates SLC7A11-mediated efferocytosis inhibition to promote wounds healing in diabetes

The healing process of chronic wounds often progresses slowly and is fraught with challenges, imposing increasing economic burdens and physical suffering on patients. Managing persistent wound inflammation and stimulating angiogenesis are crucial elements in promoting wound healing. Plants have been playing a key role in traditional medicine, and their abundant bioactive components continually inspire the development and innovation of new drugs. Isoliquiritigenin (ISL), a flavonoid compound derived from licorice roots known as chalcone, has demonstrated multifaceted pharmacological potential. However, its effects on diabetic wounds and the detailed mechanisms remain to be investigated. Through in-depth exploration using network pharmacology, we successfully predicted potential therapeutic targets of ISL for ischemic diseases. The revealed mechanisms primarily focused on the critical pathway of efferocytosis. Subsequent in vivo experiments demonstrated that ISL significantly enhanced the efferocytosis of dendritic cells (DC), improving the functional behaviors of endothelial cells. Further research indicated that ISL promoted DC efferocytosis by regulating SLC7A11-mediated glycolysis. Notably, the overexpression of SLC7A11 diminished the positive effects of ISL, suggesting a potential antagonistic role of SLC7A11 in the regulatory process. In the wounds of diabetic mice, we observed that ISL accelerated DC efferocytosis and angiogenesis, resulting in faster wound closure and better tissue repair. In summary, this study not only demonstrates the broad potential of ISL in managing diabetic wounds but also delves deeply into its mechanisms, laying a solid theoretical foundation for future clinical applications.

Investigation of antibacterial and anticancer activities of biosynthesized metal-doped and undoped zinc oxide nanoparticles.

Over the past 10 years, nanotechnology has emerged as a very promising technique for a wide range of biomedical applications. Green synthesized metal and metal oxide nanoparticles (NPs) are cheap, easy to produce in large quantities, and safe for the environment. Currently, efforts are being made to dope ZnO in order to improve its optical, electrical, and ferromagnetic qualities as well as its crystallographic quality. Actually, doping is one of the simplest methods for enhancing an NP's physicochemical characteristics because it involves introducing impure ions into the crystal lattice of the particle. In this study, the biosynthesis of zinc oxide NPs (ZnONPs) and metal-doped (Mg2+ and Ag+) ZnONPs was carried out by using aqueous and water-alcoholic extracts of Cynara scolymus L. leaves, Carthamus tinctorius L. flowers, and Rheum ribes L. (RrL) plant, which are rich in phytochemical content. Plant extracts act as a natural reducing, capping, and stabilizing agent in the production. The produced NPs were characterized using a variety of methods, such as ultraviolet-visible spectroscopy, Fourier transform infrared (FTIR) spectroscopy, dynamic light scattering (DLS), and scanning electron microscopy (SEM). The produced metal-doped and undoped ZnONPs exhibited characteristic absorption peaks between 365 and 383nm due to their surface plasmon resonance bands. SEM analysis revealed that the NPs were oval, nearly spherical, and spherical. In the FTIR spectra, the Zn-O bonding peak ranges from 400 to 700cm-1. The peaks obtained in the range of 407-562cm-1 clearly represent the Zn-O bond. In addition, the FTIR results showed that there were notable amounts of phenol and flavonoid compounds in both the prepared extract and ZnONPs. According to DLS analysis results, the size distribution of produced NPs is between 120 and 786nm. The antibacterial properties of green produced NPs on Gram-positive (Staphylococcus aureus RN4220) and Gram-negative (Escherichia coli DH10B) bacterial strains were investigated by agar well diffusion method. In studies investigating the anticancer activities of biosynthesized NPs, mouse fibroblast cells (L929) were used as healthy cells and human cervical cancer cells (HeLa) were used as cancer cells. Only the produced Ag-ZnONPs showed potent dose-dependent antibacterial activity (at concentrations higher than 100µg/mL) against Gram-positive and Gram-negative bacteria. RrL-ZnONP-600 and RrL-ZnONP-800 NPs produced with water-ethanol extract of RrL plant and calcined at 600 and 800°C were effective at high concentrations in healthy cells and at low concentrations in HeLa cancer cells, showing that they have the potential to be anticancer agents. The study's findings highlight the potential of green synthesis techniques in the production of medicinal nanomaterials for the treatment of cancer and other biological uses.

Portuguese Grapevine Leaves: A Neglected By-Product with High Potential

In Portugal, grapevine leaves are generally treated as agro-industrial waste, despite being rich in bioactive compounds that offer benefits to human health. This study compiles the most relevant and current data on the phytochemical composition and bioactive properties of grape leaves from both red and white varieties cultivated in the country. These by-products are abundant in flavonoid and non-flavonoid phenolic compounds, such as flavonols, derivatives of hydroxycinnamic acids, carotenoid pigments, and chlorophylls, as well as fatty acids, which have scientifically proven antioxidant, antimicrobial, anti-inflammatory, antidiabetic, cardio-, neuro- and hepatoprotective properties, among others. The combination of these beneficial properties, along with the low toxicity of their compounds, makes grapevine leaves a by-product with great potential for use in the food, pharmaceutical, and cosmetic industries. The key challenge is to develop sustainable methods to reintegrate this by-product into the supply chain, in alignment with the sustainability goals of the 2030 Agenda.

In silico-guided synthesis of a new, highly soluble, and anti-melanoma flavone glucoside: Skullcapflavone II-6'-O-β-glucoside.

Guided by in silico analysis tools and biotransformation technology, new derivatives of natural compounds with heightened bioactivities can be explored and synthesized efficiently. In this study, in silico data mining and molecular docking analysis predicted that glucosides of skullcapflavone II (SKII) were new flavonoid compounds and had higher binding potential to oncogenic proteins than SKII. These benefits guided us to perform glycosylation of SKII by utilizing four glycoside hydrolases and five glycosyltransferases (GTs). Findings unveiled that exclusive glycosylation of SKII was achieved solely through the action of GTs, with Bacillus subtilis BsUGT489 exhibiting the highest catalytic glycosylation efficacy. Structure analysis determined the glycosylated product as a novel compound, skullcapflavone II-6'-O-β-glucoside (SKII-G). Significantly, the aqueous solubility of SKII-G exceeded its precursor, SKII, by 272-fold. Furthermore, SKII-G demonstrated noteworthy anti-melanoma activity against human A2058 cells, exhibiting an IC50 value surpassing that of SKII by 1.4-fold. Intriguingly, no substantial cytotoxic effects were observed in a murine macrophage cell line, RAW 264.7. This promising anti-melanoma activity without adverse effects on macrophages suggests that SKII-G could be a potential candidate for further preclinical and clinical studies. The in silico tool-guided synthesis of a new, highly soluble, and potent anti-melanoma glucoside, SKII-G, provides a rational design to facilitate the future discovery of new and bioactive compounds.

Preparation and Pharmacokinetics of Brain-Targeted Nanoliposome Loaded with Rutin

Rutin is a flavonoid compound with potential for treating Alzheimer’s disease, preventing brain damage, mitigating cerebral ischemia–reperfusion injury, and exhibiting anti-glioblastoma activity. However, its efficacy is limited by its low solubility, poor bioavailability, and limited permeability across the blood–brain barrier (BBB). To enhance the bioavailability and brain-targeting ability of Rutin, transferrin-modified Rutin liposome (Tf-Rutin-Lip) was developed using liposomes as a delivery system. Rutin liposomes were prepared using the thin-film dispersion method, and the preparation conditions were optimized using the response surface methodology. Then, transferrin (Tf) was incorporated into the liposomes through covalent modification, yielding Tf-Rutin liposomes. The toxicity of these liposomes on bEnd.3 cells, as well as their impact on the tight junctions of these cells, was rigorously evaluated. Additionally, in vitro and in vivo experiments were conducted to validate the brain-targeting efficacy of the Tf-Rutin liposomes. A susceptible detection method was developed to characterize the pharmacokinetics of Tf-Rutin-Lip further. The optimized conditions for the preparation of Tf-Rutin-Lip were determined as follows: a lipid-to-cholesterol ratio of 4.63:1, a drug-to-lipid ratio of 1:45.84, a preparation temperature of 42.7 °C, a hydration volume of 20 mL, a sonication time of 10 min, a surfactant concentration of 80 mg/mL, a DSPE-MPEG-2000 concentration of 5%, and a DSPE-PEG2000-COOH to DSPE-MPEG-2000 molar ratio of 10%. The liposomes did not affect the cell activity of bEnd.3 cells at 24 h and did not disrupt the tight junction of the blood–brain barrier. Tf-modified liposomes were taken up by bEnd.3 cells, which, in turn, passed through the BBB, thus improving liposomal brain targeting. Furthermore, the results of pharmacokinetic experiments showed that the Cmax, AUC0-∞, AUC0-t, MRT0-∞, and t1/2 of Tf-Rutin-Lip increased 1.99-fold, 2.77-fold, 2.58-fold, 1.26-fold, and 1.19-fold compared to those of free Rutin solution, respectively. These findings suggest that Tf-Rutin-Lip is brain-targeted and may enhance the efficacy of Rutin in the treatment of brain disorders.

Tilianin suppresses NLRP3 inflammasome activation in myocardial ischemia/reperfusion injury via inhibition of TLR4/NF-κB and NEK7/NLRP3

Tilianin, a flavonoid compound derived from Dracocephalum moldavica L., is recognized for its diverse biological functionalities, in particular alleviating myocardial ischemia-reperfusion injury (MIRI). There is ample evidence suggesting that the NLRP3 inflammasome has a significant impact on the development of MIRI. In this study, rats undergoing the ligation and subsequent release of the left anterior descending (LAD) coronary artery and H9c2 cardiomyocytes subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) were used to investigate the effects of tilianin on NLRP3 inflammasome and its anti-MIRI mechanisms. Upon reperfusion, the rats were intraperitoneally injected with tilianin at doses of 3, 10, 30 mg/kg. H9c2 cells were treated with tilianin at concentrations of 10, 30, and 50 μg/mL. Echocardiography, TTC staining and TUNEL staining demonstrated that tilianin remarkably improved cardiac function and mitigated myocardial damage in MIRI rats. Additionally, notable inflammatory response reduction by tilianin was evidenced by subsequent hematatoxylin-eosin (HE) staining, inflammatory cytokines assay, and quantitative proteomics. Further western blotting analysis and immunofluorescence staining showed tilianin decreased the levels of TLR4, p-NF-κB, NLRP3, and ASC in MIRI rats and H9c2 cells exposed to OGD/R, alongside a significant reduction in cleaved gasdermin D, mature IL-1β and IL-18. Molecular docking, cellular thermal shift assay (CETSA) and co-immunoprecipitation (co-IP) assay revealed that tilianin impeded the interaction between NLRP3 and NEK7. Taken together, tilianin protects cardiomyocytes from MIRI by suppressing NLRP3 inflammasome through the inhibition of the TLR4/NF-κB signaling pathway and the disruption of the NEK7/NLRP3 interface. These findings underscore the potential of tilianin as a promising therapeutic candidate for MIRI.

Acacetin alleviates rheumatoid arthritis by targeting HSP90 ATPase domain to promote COX-2 degradation

BackgroundInflammation plays a significant role in initiating and sustaining rheumatoid arthritis (RA). Acacetin, a natural flavonoid compound, exhibits excellent anti-inflammatory effects specifically for RA. However, its relevant targets and molecular mechanisms remain to be elucidated. PurposeThis study aims to investigate the mechanism of acacetin in the therapeutic efficacy of acacetin in RA and search for new therapeutic options for RA treatment. MethodsA collagen-induced RA mouse model was established to evaluate the therapeutic effect of acacetin. Acacetin functional probes were synthesized to capture potential target proteins in RAW264.7 cells. Various small molecule-protein interaction methods were conducted to verify the binding of acacetin to target protein. Molecular docking and site directed mutagenesis tests were performed to analyze the specific binding sites. Co-immunoprecipitation, immunofluorescence assay and western blot were engineered to explore the effect of acacetin on COX-2 degradation by targeting HSP90. ResultsAcacetin specifically binds to the ATP domain of HSP90, to facilitate the dissociation between HSP90 and COX-2, inducing the ubiquitin-degradation of COX-2 in macrophages. Acacetin suppressed the production of pro-inflammatory cytokines, as well as inflammatory related pathways, exerting excellent anti-inflammatory effects in RA. ConclusionsThis research proved that acacetin, a novel HSP90 ATPase inhibitor, inhibits the functional folding of the client protein COX-2, promoting its ubiquitin degradation for anti-inflammation. Targeting HSP90 is a viable strategy to inhibit inflammation, affording a distinct way to managing joint inflammation and pains associated with RA.

Investigation of the Anticholinesterase and Antioxidant Activity of Several Iranian Thymus caramanicus Populations

Background: Thymus extracts have become attractive targets for screening bioactive compounds with potential applications in pharmaceuticals, food, and cosmetics industries. Objectives: This is the first report assessing the anticholinesterase and antioxidant activities, along with total phenolic and flavonoid contents (TPC and TFC), of hydroethanolic extracts from six populations of Thymus caramanicus Jalas at vegetative and flowering stages, collected from different regions in Kerman province, Iran. Methods: The anticholinesterase and antioxidant activity, as well as TPC and TFC of T. caramanicus hydroethanolic extracts, were evaluated using Ellman, DPPH, Folin-Ciocalteu, and aluminum chloride assays, respectively. Results: All extracts inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes, with most showing a stronger effect on AChE. The extract T2-F exhibited the highest anti-AChE (IC50: 28.74 ± 0.21 µg/mL) and anti-BuChE (IC50: 65.49 ± 0.81 µg/mL) activities. The DPPH results indicated overall suitable antioxidant activity, with T4-F showing the highest antioxidant capacity (IC50: 16.22 ± 0.07 µg/mL), though about 4.2 times lower than ascorbic acid. The TPC (76.60 ± 0.98 - 211.73 ± 2.13 mg GAE/g extract) and TFC (19.15 ± 0.09 - 53.90 ± 0.13 mg QE/g extract) analyses revealed that T6-V and T5-F are rich sources of polyphenolic and flavonoid compounds. Pearson’s correlation analysis showed no direct correlation between TPC and TFC with their anticholinesterase and antioxidant activities. Conclusions: The hydroethanolic extracts of T. caramanicus demonstrated significant anticholinesterase and antioxidant activities, making them promising candidates for further studies aimed at developing therapeutic compounds with dual anticholinesterase and antioxidant properties, potentially for treating Alzheimer's disease (AD).

Investigating the Inhibitory Potential of Flavonoids against Aldose Reductase: Insights from Molecular Docking, Dynamics Simulations, and gmx_MMPBSA Analysis.

Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia, with aldose reductase playing a critical role in the pathophysiology of diabetic complications. This study aimed to investigate the efficacy of flavonoid compounds as potential aldose reductase inhibitors using a combination of molecular docking and molecular dynamics (MD) simulations. The three-dimensional structures of representative flavonoid compounds were obtained from PubChem, minimized, and docked against aldose reductase using Discovery Studio's CDocker module. The top 10 compounds Daidzein, Quercetin, Kaempferol, Butin, Genistein, Sterubin, Baicalein, Pulchellidin, Wogonin, and Biochanin_A were selected based on their lowest docking energy values for further analysis. Subsequent MD simulations over 100 ns revealed that Daidzein and Quercetin maintained the highest stability, forming multiple conventional hydrogen bonds and strong hydrophobic interactions, consistent with their favorable interaction energies and stable RMSD values. Comparative analysis of hydrogen bond interactions and RMSD profiles underscored the ligand stability. MMPBSA analysis further confirmed the significant binding affinities of Daidzein and Quercetin, highlighting their potential as aldose reductase inhibitors. This study highlights the potential of flavonoids as aldose reductase inhibitors, offering insights into their binding interactions and stability, which could contribute to developing novel therapeutics for DM complications.

Mitigation strategy of saline stress in Fragaria vesca using natural and synthetic brassinosteroids as biostimulants.

Bassinosteroids (BRs) can induce plant defence responses and promote plant growth. In this work, we evaluated the effect of a natural (EP24) and a synthetic (BB16) brassinosteroid on strawberry (Fragaria vesca ) plants exposed to saline stress. Treated plants showed higher shoot dry weight and root growth compared to untreated control plants. In BR-treated plants, crown diameters increased 66% and 40%, leaf area 148% and 112%, relative water content in leaves 84% and 61%, and SPAD values 24% and 26%, in response to BB16 and EP24, respectively. A marked stomatal closure, increased leaflet lignification, and a decrease in cortex thickness, root diameter and stele radius were also observed in treated plants. Treatments also reduces stress-induced damage, as plants showed a 34% decrease in malondialdehyde content and a lower proline content compared to control plants. A 22% and 15% increase in ascorbate peroxidase and total phenolic compound activities was observed in response to BB16, and a 24% increase in total flavonoid compound in response to both BRs, under stress conditions. These results allow us to propose the use of BRs as an environmentally safe crop management strategy to overcome salinity situations that severely affect crop yield.

Metabolic insights into the mechanism of soybean reddening during storage.

Soybean reddening during storage and transportation has caused great concern due to the serious economic loss. However, the mechanism of reddening has not been clearly elucidated. In this study, metabolomics was employed to investigate the reasons for soybean reddening during storage. The results of multivariate statistical analysis showed that the metabolite level of red soybean was significantly different from that of normal soybean. The differentially expressed metabolites were mainly enriched by biosynthesis of secondary metabolites and amino acid metabolism. Metabolism analysis showed that the biosynthesis of cyanidin and betalains was enhanced in reddening soybean. In addition, it was found that phenolic and flavonoid compounds decreased, while quinones, furans and 5-hydroxymethylfurfural increased in reddening soybeans compared to normal soybeans. The upregulation of cyanidin and betalains was the main reason for soybean reddening. Besides, the oxidation of phenols and flavonoids, as well as Maillard reaction, also contributed to the color change. © 2024 Society of Chemical Industry.

The Influence of Sodium Humate on the Biosynthesis and Contents of Flavonoid Constituents in Lemons

Sodium humate (SH) is the sodium salt of humic acid. Our previous research has demonstrated that SH has the ability to enhance the levels of total flavonoids in various parts of lemons, including the leaves, peels, pulps, and seeds, thereby improving the quality of lemons. In the current study, the regulation effect of SH on the biosynthesis and content of lemon flavonoid compounds was examined using transcriptome sequencing technology and flavonoid metabolomic analysis. Following SH treatment, the transcriptome sequencing analysis revealed 320 differentially expressed genes (DEGs) between samples treated with SH and control (CK) samples, some of which were associated with the phenylalanine pathway by KEGG annotation analysis. The levels of seven flavonoid compounds identified in lemon peels were observed to increase, and eriocitrin and isoorientin were identified as differential metabolites (DMs, VIP > 1) using OPLS-DA analysis. The integrated analysis of transcriptomics and flavonoid metabolomics indicates that SH treatment induces alterations in gene expression and metabolite levels related to flavonoid synthesis. Specifically, SH influences flavonoid biosynthesis by modulating the activity of key enzymes in the phenylalanine pathway, including HCT (O-hydroxycinnamoyltransferase) and F5H (ferulate-5-hydroxylase).

Fisetin reduces ovalbumin-triggered airway remodeling by preventing phenotypic switching of airway smooth muscle cells

BackgroundThe transformation of airway smooth muscle cells (ASMCs) from a quiescent phenotype to a hypersecretory and hypercontractile phenotype is a defining feature of asthmatic airway remodeling. Fisetin, a flavonoid compound, possesses anti-inflammatory characteristics in asthma; yet, its impact on airway remodeling and ASMCs phenotype transition has not been investigated.ObjectivesThis research seeked to assess the impact of fisetin on ovalbumin (OVA) induced asthmatic airway remodeling and ASMCs phenotype transition, and clarify the mechanisms through network pharmacology predictions as well as in vivo and in vitro validation.MethodsFirst, a fisetin-asthma-ASMCs network was constructed to identify potential targets. Subsequently, cellular and animal studies were carried out to examine the inhibitory effects of fisetin on airway remodeling in asthmatic mice, and to detemine how fisetin impacts the phenotypic transition of ASMCs.ResultsNetwork analysis indicated that fisetin might affect asthma via mediating the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) pathway. Intraperitoneal administration of fisetin in vivo reduced airway inflammation and remodeling, as shown by reduced inflammatory cells, decreased T helper type 2 (Th2) cytokine release, diminished collagen accumulation, mitigated airway smooth muscle thickening, and decreased expression of osteopontin (OPN), collagen-I and α-smooth muscle actin (α-SMA). Moreover, fisetin suppressed the PI3K/AKT pathway in asthmatic lung tissue. According to the in vitro data, fisetin downregulated the expression of the synthetic phenotypic proteins OPN and collagen-I, contractile protein α-SMA, and inhibited cellular migration, potentially through the PI3K/AKT pathway.ConclusionThese results suggest that fisetin inhibits airway remodeling in asthma by regulating ASMCs phenotypic shift, emphasizing that fisetin is a promising candidate for the treatment of airway smooth muscle remodeling.

Revealing the molecular mechanism of baohuoside I for the treatment of breast cancer based on network pharmacology and molecular docking

Ethnopharmacological relevanceIn Traditional Chinese Medicine (TCM), there are many prescriptions for treating breast cancer (BC) that utilize the herb Epimedium brevicornum Maxim, which warms and replenishes kidney yang. Baohuoside I (BI) is a flavonoid compound found in Epimedium brevicornum Maxim. As a single glycoside, it is not easily hydrolyzed in the intestine and is typically absorbed as a precursor. As a natural product with potential anti-cancer properties, studies have shown that BI possesses anti-cancer activity and can inhibit the invasion and migration of BC cells. However, its underlying mechanisms remain unclear, thus further research is needed to validate its modern mechanisms for traditional uses. Aim of the studyThis study aimed to explore the regulatory mechanism of BI in the signaling pathways of BC cells through network pharmacology (NP), molecular docking (MD) techniques and cellular experiments. MethodsPotential targets were predicted using public databases, and a protein-protein interaction (PPI) network was constructed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. Key signaling pathways were validated through MD techniques, cellular experiments, RNA interference and Western blot (WB) analysis. ResultsTreatment-associated targets included SRC, MAPK1, HSP90AA1, PIK3CA, TP53, AKT1, and EGFR. GO enrichment, KEGG enrichment analyses, and MD results indicated that BI exerts its anti-breast cancer effects by inhibiting the tyrosine kinase activity of EGFR, as well as through downstream MAPK signaling pathway and PI3K-Akt signaling pathway pathways. In vitro experiments confirmed that BI primarily induce cell apoptosis through the EGFR-mediated MAPK signaling pathway and PI3K-Akt signaling pathway. ConclusionBI can inhibit EGFR activation and promote BC cell apoptosis through the MAPK signaling pathway and PI3K-Akt signaling pathway, thereby exerting therapeutic effects on BC. This study not only provides experimental evidence for the accuracy of NP but also offers an effective approach for rational utilization of Baohuoside I-like flavonoid compounds as anti-breast cancer drugs.

Icariin promotes skeletal muscle mitochondrial biogenesis by the AMPK-PPARδ-PGC-1α signaling pathway: A potential mechanism for beneficial muscle function homeostasis

Mitochondrial biogenesis is a key factor in regulating skeletal muscle function and homeostasis. At present, a growing number of natural polyphenols, flavonoids and other compounds have been reported to have the function of regulating skeletal muscle oxidative metabolism. Here, we aimed to explore the effect of the flavonoid compound icariin purified from Epimedium koreanum Nakai in regulating mitochondrial biogenesis in mice and C2C12 myotubes. We found that icariin elevated the inverted suspension time by 1.72-fold and the distance run on the treadmill by 1.52-fold in mice. Daytime respiratory exchange ratio was significantly lower in mice after 8 weeks of icariin treatment compared to control groups. Icariin activated the mitochondrial biogenetic signaling pathway and mitochondrial marker expression, and the mitochondrial size of gastrocnemius and soleus was increased by 2.3-fold and 2.0-fold in mice, respectively. In addition, icariin elevated mitochondrial DNA copy number by 1.41-fold and 1.54-fold in gastrocnemius and C2C12 myotube cells, respectively. In vitro studies showed that inhibition of p-AMPK and PPARδ could attenuate ICA-regulated mitochondrial biogenetic pathway. Our study suggests that icariin promotes mitochondrial biogenesis and exercise endurance through AMPK-PPARδ-PGC-1α signaling pathway in C57BL/6 J mice skeletal muscle, indicating that icariin may be able to regulate muscle mitochondria function as an exercise mimetic.

Stevia By-product Fraction has Antioxidant Capacity and has been Evaluated for its Antihyperglycemic and Antilipid Potential

Introduction/Objective: The ethanolic pretreatment of stevia leaves is considered ecologically favorable and increases its yield, purity level, and sensory profile of sweeteners. We investigated the by-product generated so that we can provide a viable and applicable destination to effectively contribute to the production and industrial chain of stevia sweeteners. Recently, an antioxidant and antidiabetic fraction was obtained through stevia methanolic extraction. However, this process is costly, has a low yield, and is non-green. In this study, we got an antioxidant fraction of stevia from its pretreatment by-product, the ethanolic extract, characterized its bioactive compounds – mainly phenolic acids and flavonoids – and evaluated its antidiabetic and antilipid capacity. Methods: The ethanolic extract was fractionated, then the ethyl acetate fraction was microencapsulated. Physicochemical, Mass Spectrometry (UHPLC/MS-MS), scanning electron microscopy, microencapsulation efficiency, and antioxidant capacity analyses were carried out. The antioxidant capacity was evaluated. Antihyperglycemic capacity was assessed by inhibition of α-glucosidase and α-amylase. For antilipid potential, inhibition of pancreatic lipase was measured. Results: Antioxidant potential was observed mainly in the fraction. Microencapsulation improved the stability of the fraction. Mass spectrometry allowed comparison with phenolic and flavonoid compounds from the methanolic and ethanolic fractions of the by-product. Many compounds were coincident, which may explain the similar antioxidant capacity found. The samples showed more than 90% inhibition of alpha-glucosidase, which may indicate potential antidiabetic activity. All samples showed inhibition of the pancreatic lipase enzyme higher than 80%, reaching 91.05% for the free fraction. Conclusion: This study represented the recovery of a by-product and showed that this antioxidant fraction deserves further investigation for its bioactive potential, especially antioxidant, antidiabetic, and anti-lipid.

Hyaluronic Acid-Modified Luteolin-Copper Complex Nanodelivery System for Bacterial Prostatitis.

Bacterial prostatitis is a common disease of the male genitourinary system, which seriously affects the normal life and health of male patients. Antibiotics are commonly used in the clinical treatment of bacterial prostatitis, but the efficacy of fluoroquinolones is gradually declining due to the increasing drug resistance of bacteria. Hence, it is necessary to find new antibacterial drugs to treat bacterial prostatitis. Luteolin is a natural flavonoid compound with many pharmacological activities such as antibacterial and anti-inflammatory activities, but its poor water solubility and low structural stability seriously limit its clinical application. In this study, we designed a targeting drug delivery system via a luteolin-copper complex grafted with hyaluronic acid. The results of the characterization proved the successful synthesis of the system. The results of the in vitro performance test show that the system has a good antibacterial effect and excellent blood compatibility and can be effectively released under different pH conditions. The prepared nanodrug delivery system not only provides a new idea for the treatment of bacterial prostatitis but also lays a theoretical and practical foundation for the wide application of luteolin in clinical practice.

Flavonoids as potential SARS-CoV-2 main protease inhibitors: In vitro activity evaluation, molecular docking, 3D-QSAR investigation and synthesis

The damage to public health posed by the COVID-19 epidemic remains non-negligible, and research into highly effective antiviral drugs is key to addressing the epidemic. The main protease (Mpro) is critical for SARS-CoV-2 replication and acts as an effective target for drug development. To date, many flavonoid compounds have been reported to exhibit inhibition of Mpro, and flavonoid structures are informative for the development of new inhibitors. In the present study, we first evaluated the ability of 35 flavonoid compounds to bind Mpro and found that the hydrophobic interaction generated between the benzene ring and the residues may be the main source of binding force. The in vitro inhibitory activity of these compounds was tested by the FRET method, and most of them showed significant inhibition of Mpro. Preliminary analysis revealed that the presence of the glycosidic group was detrimental to the activity of the compounds, in addition the position of the hydroxyl substituent had an effect on the activity of the compounds. Reliable and predictive CoMFA (q2 = 0.541, r2 = 0.998, SEE = 0.039) and CoMISA (q2 = 0.554, r2 = 0.999, SEE = 0.034) models were developed, and the compounds were analyzed by 3D-QSAR with modeled steric, electrostatic, hydrogen bond donor, and hydrophobic fields. A series of compounds were synthesized and characterized, which showed similar experimental and predicted activities, with the activity of 15d (IC50 = 0.74 ± 0.04 uM) exceeding that of the template molecule 15 (0.98 ± 0.13 uM). Subsequently, molecular docking revealed the binding mode of 15d to Mpro and verified the predictions of steric, hydrogen bond donor, and hydrophobic field. In conclusion, these findings provide ideas for subsequent structural studies of flavonoids that could be used in the development of flavonoid-type SARS-CoV-2 Mpro inhibitors.

Phytochemical analysis and in vitro biological activity assessment of extracts from Micromeria myrtifolia

ABSTRACT In this study, the antioxidant capacity, the effect on anti-acetylcholinesterase and anti-urease enzyme inhibition, and kidney stone-reducing effects of different extracts from M.myrtifolia. In addition, the phytochemical content of the bioactive methanol extract was analyzed by HPLC-DAD. The methanol extract showed strong DPPH (IC50:0.036 mg/mL) radical scavenging, Cu (II) ion (6.535 mmTroloxE) and Fe3+ (6.476 FeSO4) ion reducing antioxidant activity compared to other extracts. The methanol extract contained the highest amount of phenolic (400 mgGAE) and flavonoid (2.519 QuE) compounds. Moreover, the methanol extract had significant anticholinesterase (78.935%), anti-urease (71.014%) and calcium oxalate anti-crystallization (18.22%, 37.427%) activities. The findings show that all extracts exhibited varying amounts of antibacterial activity against Staphylococcus aureus. The bioactive methanol extract contained rosmarinic acid (31.35 µg), quercetin (12.99 µg) and chlorogenic acid (3.55 µg). The analyzed compounds are thought to contribute significantly to the pharmacological effect of the methanol extract.