Synergistic actions of three MYB transcription factors underpins the high accumulation of myricetin in Morella rubra.

Flavonols are health-promoting bioactive compounds important for human nutrition, health, and plant defense. The transcriptional regulation of kaempferol and quercetin biosynthesis has been studied extensively, while little is known about the regulatory mechanisms underlying myricetin biosynthesis, which has strong antioxidant, anticancer, antidiabetic, and anti-inflammatory activities. In this study, the flavonol-specific MrMYB12 in Morella rubra preferred activating the promoter of flavonol synthase 2 (MrFLS2) (6.4-fold) rather than MrFLS1 (1.4-fold) and upregulated quercetin biosynthesis. Furthermore, two SG44 R2R3-MYB members, MrMYB5 and MrMYB5L, were identified by yeast one-hybrid library screening using the promoter of flavonoid 3',5'-hydroxylase (MrF3'5'H), and transcript levels of these R2R3-MYBs were correlated with accumulation of myricetin derivatives during leaf development. Dual-luciferase and electrophoretic mobility shift assays demonstrated that both MrMYB5 and MrMYB5L could bind directly to MYB recognition sequence elements in promoters of MrF3'5'H or MrFLS1 and activate their expression. Protein-protein interactions of MrMYB5 or MrMYB5L with MrbHLH2 were confirmed by yeast two-hybrid and bimolecular fluorescence complementation assays. MrMYB5L-MrbHLH2 showed much higher synergistic activation of MrF3'5'H or MrFLS1 promoters than MrMYB5-MrbHLH2. Studies with Arabidopsis thaliana homologs AtMYB5 and AtTT8 indicated that similar synergistic regulatory effects occur with promoters of MrF3'5'H or MrFLS1. Transient overexpression of MrMYB5L-MrbHLH2 in Nicotiana benthamiana induced a higher accumulation of myricetin derivatives (57.70 µg g-1 FW) than MrMYB5-MrbHLH2 (7.43 µg g-1 FW) when MrMYB12 was coexpressed with them. This study reveals a novel transcriptional mechanism regulating myricetin biosynthesis with the potential use for future metabolic engineering of health-promoting flavonols.

Myricetin reduces platelet PANoptosis in sepsis to delay disseminated intravascular coagulation.

Sepsis is a severe inflammatory disease characterized by cytokine storm, often accompanied by disseminated intravascular coagulation (DIC). PANoptosis is a novel form of cell death triggered by cytokine storms, characterized by a cascade reaction of pyroptosis, apoptosis, and necroptosis. It exists in septic platelets and is closely associated with the onset and progression of DIC. However, there remains an unmet need for drugs targeting PANoptosis. The anti-PANoptosis effect of myricetin was predicted using network pharmacology and confirmed through molecular docking. In vitro platelet activation models demonstrated that myricetin significantly attenuated platelet particle release, integrin activation, adhesion, spreading, clot retraction, and aggregation. Moreover, in a sepsis model, myricetin reduced inflammatory infiltration in lung tissue and platelet activation while improving DIC. Additionally, whole blood sequencing samples from sepsis patients and healthy individuals were analyzed to elucidate the up-regulation of the PANoptosis targets. Our findings demonstrate the inhibitory effect of myricetin on septic platelet PANoptosis, indicating its potential as a novel anti-cellular PANoptosis candidate and therapeutic agent for septic DIC. Furthermore, our study establishes a foundation for utilizing network pharmacology in the discovery of new drugs to treat various diseases.

Myricetin and myricitrin indirectly and directly increases uncoupling protein-1 mRNA expression in C3H10T1/2 beige adipocytes.

In thermogenic brown and beige adipocytes, the proton gradient formed by energy derived from nutrients such as lipids and carbohydrates is consumed by uncoupling protein-1 (UCP-1), resulting in thermogenesis without ATP production in the mitochondria. Accordingly, increased UCP-1 expression represents a crucial aspect of dietary management for individuals with overweight and obesity. Myricetin and its glycoside, myricitrin, are food-derived flavonoids that possess various beneficial effects. This is the first study to examine the effects of myricetin and myricitrin on the inflammation-inhibited expression of Ucp-1 using a modified cell-based assay with conditioned medium (CM). The CM derived from lipopolysaccharide (LPS)-activated RAW264.7 macrophages was observed to inhibit the Ucp-1 expression induced by adrenergic stimulation in 10T1/2 adipocytes. Conversely, the CM derived from activated macrophages treated with myricetin or myricitrin reversed this inhibition of Ucp-1 expression. Subsequently, the direct effects of both the compounds on basal and adrenaline-induced expression of Ucp-1 were investigated. In contrast to a previous report, myricetin and myricitrin did not increase the basal Ucp-1 mRNA expression in 10T1/2 adipocytes when treated during the differentiation-promoting period. However, we have found for the first time that both compounds enhanced the adrenergic sensitivity of 10T1/2 adipocytes when treated during the differentiation-inducing period. These results indicate that myricetin and myricitrin have indirect effects on inflammation-induced suppression and direct effects on adrenergic sensitivity, suggesting a novel mechanism that both compounds increase Ucp-1 expression in vivo by both indirect and direct effects, rather than by affecting basal expression.

Myricetin inhibits 4 T1 breast tumor growth in mice via induction of Nrf-2/GPX4 pathway-mediated Ferroptosis.

Ferroptosis is a recently identified form of programmed cell death that is iron-dependent and closely involved in the pathogenesis of breast cancer. Past studies have identified myricetin as being able to inhibit breast cancer growth through its targeting of apoptotic mechanisms, but the precise mechanisms whereby it exerts its antitumoral effects in breast cancer remain to be characterized in detail. Here, the effects of myricetin on the induction of ferroptosis in breast cancer cells were investigated. It was found that myricetin was able to significantly inhibit 4 T1 tumor cell viability and colony forming activity, increasing the level of MDA, Fe2+, and ROS within these cells. From a mechanistic perspective, myricetin was found to induce ferroptotic 4 T1 cell death via downregulating Nrf-2 and GPX4. In vivo experimentation demonstrated that myricetin treatment was sufficient to reduce the growth of subcutaneous breast tumors in female mice as evidenced by decreases in tumor weight and volume, while significantly inhibiting Nrf-2 and GPX4 expression within the tumors of treated mice. Myricetin is capable of readily suppressing breast tumor growth in mice via the induction of ferroptotic activity through the Nrf-2/GPX4 pathway. Myricetin may thus offer utility as a therapeutic agent for the management of breast cancer in clinical settings.

The selective proapoptotic impact of the myricetin-loaded alginate-cellulose hybrid nanocrystals (MAC-NCs) on the human AGS gastric cancer cells.

BACKGROUND: Myricetin, a flavanol present in fruits, tea, and vegetables, has the potential to reduce chronic diseases like gastric cancer by promoting cell death and stopping cell growth. However, its limited bioactivity due to its short lifespan and poor solubility in water has been a challenge. The current research focuses on incorporating myricetin into alginate-cellulose hybrid nanocrystals to enhance its selective proapoptotic effects on human AGS gastric cancer cells. METHODS: MAC-NCs, myricetin-loaded alginate-cellulose hybrid nanocrystals, were synthesized using a combined co-precipitation/ultrasonic homogenization method and characterized through Dynamic Light Scattering (DLS), Fourier Transform Infrared Spectroscopy (FTIR), Field Emission Scanning Electron Microscope (FESEM), and Zeta-potential analyses. Their cytotoxic activity was tested on cancerous (AGS) and normal (Huvec) cells, revealing selective toxicity. Apoptotic markers, Caspase 8 and Caspase 9, gene expression was measured, and cell death type was confirmed using DAPI staining and flow cytometry on AGS cells. RESULTS: Synthesized MAC-NCs, measuring 40 nm, showed significant selective toxicity on human gastric cells (IC50 of 31.05 µg/mL) compared to normal endothelial cells (IC50 of 214.26 µg/mL). DAPI and annexin flow cytometry revealed increased apoptotic bodies in gastric cells, indicating apoptosis. However, the apoptosis was found to be independent of Caspase-8 and Caspase-9. CONCLUSION: The current study provides critical insights into the therapeutic potential of MAC-NCs for gastric cancer treatment. Based on the notable induction of apoptosis in the AGS cancer cell line, the synthesized MAC-NCs exhibit promising potential as a selective anti-gastric cancer agent. However, further in-vivo studies are necessary to confirm and quantify the nanoparticle's selective toxicity and pharmaceutical properties in future investigations.

Unveiling myricetin's pharmacological potency: A comprehensive exploration of the molecular pathways with special focus on PI3K/AKT and Nrf2 signaling.

Myricetin can be found in the traditional Chinese medicinal plant, Myrica rubra. Myricetin is a flavonoid that is present in many vegetables, fruits, and plants and is considered to have strong antioxidant properties as well as a wide range of therapeutic applications. Growing interest has been piqued by its classification as a polyphenolic molecule because of its potential therapeutic benefits in both the prevention and management of numerous medical conditions. To clarify myricetin's traditional medical uses, modern research has investigated various pharmacological effects such as antioxidant, anticancer, anti-inflammation, antiviral, antidiabetic, immunomodulation, and antineurodegenerative effects. Myricetin shows promise as a nutritional flavonol that could be beneficial in the prevention and mitigation of prevalent health conditions like diabetes, cognitive decline, and various types of cancer in humans. The findings included in this study indicate that myricetin has a great deal of promise for application in the formulation of medicinal products and nutritional supplements since it affects several enzyme activities and alters inflammatory markers. However, comprehensive preclinical studies and research studies are necessary to lay the groundwork for assessing myricetin's possible effectiveness in treating these long-term ailments. This review summarizes both in vivo and in vitro studies investigating myricetin's possible interactions through the nuclear factor-E2-related factor 2 (Nrf2) as well as PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B) signaling pathways in an attempt to clarify the compound's possible clinical applicability across a range of disorders.

Investigating the potent TOPO IIα inhibitors in breast cancer through the study of computational drug discovery research approaches.

Breast cancer (BC) is the second-leading cause of cancer after lung cancer. The disease has affected millions of people and resulted in many deaths. In the metastasis of breast cancer cells, Topoisomerase IIα plays a vital role. Therefore, this investigation aims to identify potential flavonoid compounds against BC by inhibiting this enzyme at an early stage. Based on previous studies, we selected and screened several plant-derived flavonoid compounds with potential anti-breast cancer activity using PyRx 0.8 and Schrodinger applications for preliminary molecular docking: the highest docking scores of Myricetin (-11.6 kcal/mol) and Quercetin (-10.0 kcal/mol). Next, we evaluated the top four compounds on the Way2Drug server to complete the cytotoxicity evaluation, which demonstrated anti-cancer and anti-breast cancer activity in various cell lines. According to pharmacokinetics studies, four compounds exhibited outstanding values and functioned similar to drug-like molecules. Moreover, Myricetin, Quercetin, and Morin displayed the highest number of hydrogen bonds, with the corresponding receptor forming residues asn120, thr147, and lys168. The protein-ligand complexes were validated using the Desmond simulator, and their data were compared to the anti-breast cancer drug Doxorubicin. In the simulation analysis, various parameters were evaluated, including RMSD, RMSF, Rg, SASA, MolSA, PSA, and hydrogen bond interaction. Finally, validated our dynamic simulation result with MM-GBSA operation, and Myricetin and Quercetin had the greatest score of -72.74344651, -66.66771823 kcal/mol, which is outstanding than the control drug. Hence, the computational research approach determined that Myricetin, Quercetin, and Morin could be industrially developed for the alternative treatment of breast cancer following additional confirmation from animal and cell line studies.

Myricetin Restores Autophagy to Attenuate Lumbar Intervertebral Disk Degeneration Via Negative Regulation of the JAK2/STAT3 Pathway.

Autophagy is a critical player in lumbar intervertebral disk degeneration (IDD), and autophagy activation has been suggested to prevent the apoptosis of nucleus pulposus cells (NPCs). Myricetin has anti-cancer, anti-inflammatory, and antioxidant potentials and can activate autophagy. Thus, this study focused on the roles and mechanisms of myricetin in IDD. A puncture-induced rat IDD model was established and intraperitoneally injected with 20-mg/kg/day myricetin. Histopathological changes of intervertebral disks (IVDs) were assessed by hematoxylin and eosin staining and Safranin O/Fast Green staining. The isolated NPCs from IVDs of healthy rats were stimulated with IL-1ß to mimic IDD-like conditions. The roles of myricetin in cell apoptosis, extracellular matrix (ECM) degradation, autophagy repression, and the JAK2/STAT3 pathway activation were examined by cell counting kit-8, flow cytometry, western blotting, real-time quantitative polymerase chain reaction, and immunofluorescence staining. Myricetin treatment attenuated the apoptosis and ECM degradation, and enhanced autophagy in the IL-1ß-treated NPCs, whereas the myricetin-mediated protection was limited by autophagy inhibition. Mechanistically, myricetin activated autophagy through blocking the JAK2/STAT3 signaling. In vivo experiments revealed that intraperitoneal injection of myricetin activated NPC autophagy to relieve puncture injury in rats. Myricetin prevents IDD by attenuating NPC apoptosis and ECM degradation through blocking the JAK2/STAT3 pathway to enhance autophagy.

Myricetin Protects Against Rat Intervertebral Disc Degeneration Partly Through the Nrf2/HO-1/NF-κB Signaling Pathway.

Intervertebral disc (IVD) degeneration (IDD) is a prevalent musculoskeletal disorder. Nucleus pulposus cells (NPCs) play a significant role in the normal functioning of the IVD. Myricetin is an agent that exerts anti-inflammatory and antioxidant effects in various pathological conditions. Here, we investigated the ameliorative effects of myricetin on the IVD degeneration. NPCs were obtained from the IVD of rats, and were treated with myricetin (0, 5, 10, 15, 20 µM) for 24 h before 20 ng/mL IL-1ß stimulation. RT-qPCR, western blotting, and ELISA were applied to evaluate the levels of inflammatory factors (iNOS, COX-2, TNF-α, IL-6, PGE2, and Nitrite) and extracellular matrix (ECM)-associated components (MMP13, ADAMTS-5, aggrecan, and collagen II) in NPCs. Activation status of related signaling pathways (NF-κB and Nrf2) was determined using western blotting and immunofluorescence staining. Experimental rat models of IDD were established using a needle puncture method. Myricetin (20 mg/kg) was administrated intraperitoneally, and the degeneration was evaluated using histopathological analysis. Myricetin treatment attenuated the IL-1ß-induced production of inflammatory factors in NPCs. Downregulation of aggrecan and collagen II as well as upregulation of MMP-13 and ADAMTS-5 in NPCs caused by IL-1ß was reversed by myricetin treatment. Mechanistically, myricetin blocked NF-κB signaling by activation of Nrf2 in IL-1ß-stimulated NPCs. Moreover, inhibition of Nrf2 reversed the protective effects of myricetin in NPCs. The in vivo experiments showed that myricetin ameliorated the IDD progression in rats. The present work suggests that Nrf2 is involved in the pathogenesis of IDD and shows the protective effects as well as the underlying mechanism of myricetin on Nrf2 activation in NPCs.

Preparation of the Myricetin-Loaded PEGylated Niosomes and Evaluation of their in†vitro Anti-Cancer Potentials.

Several edible plants contain flavonoids, including myricetin (Myr), which perform a wide range of biological activities. Myr has antitumor properties against various tumor cells. In this study Myr-loaded PEGylated niosomes (Myr-PN) were prepared and their anti-cancer activities were evaluated in vitro. Myr-PNs were prepared as a tool for drug delivery to the tumor site. Myr-PN was characterized in terms of size, zeta potential, and functional groups using dynamic light scattering (DLS), Fourier-transform infrared spectroscopy (FTIR), and field emission scanning electron microscopy (SEM). The Myr-PN size was 241 nm with a polydispersity index (PDI) of 0.20, and zeta potential -32.7±6.6 mV. Apoptotic properties of Myr-PN against normal and cancer cell lines were determined by flow cytometry and real-time quantitative PCR. Cancer cells showed higher cytotoxicity when treated with Myr-PN compared with normal cells, indicating that the synthesized nanoparticles pose no adverse effects. Apoptosis was induced in cells treated with 250 µg/mL of Myr-PN, in which 45.2 % of cells were arrested in subG1, suggesting that Myr-PN can induce apoptosis. In vitro, the synthesized Myr-PN demonstrated potent anticancer properties. Furthermore, more research should be conducted in vitro and in vivo to study the more details of Myr-PN anti-cancer effects.

Preparation, characterisation, and pharmacodynamic study of myricetin pH-sensitive liposomes.

AIMS: Myricetin (MYR) was incorporated into pH-sensitive liposomes in order to improve its bioavailability and anti-hyperuricemic activity. METHODS: The MYR pH-sensitive liposomes (MYR liposomes) were prepared using thin film dispersion method, and assessed by particle size (PS), polydispersed index (PDI), zeta potential (ZP), encapsulation efficiency, drug loading, and in vitro release rate. Pharmacokinetics and anti-hyperuricemic activities were also evaluated. RESULTS: The PS, PDI, ZP, encapsulation efficiency, and drug loading of MYR liposomes were 184.34 ± 1.05 nm, 0.215 ± 0.005, -38.46 ± 0.30 mV, 83.42 ± 1.07%w/w, and 6.20 ± 0.31%w/w, respectively. The release rate of MYR liposomes was higher than free MYR, wherein the cumulative value responded to pH. Besides, the Cmax of MYR liposomes was 4.92 ± 0.20 µg/mL. The level of uric acid in the M-L-H group (200 mg/kg) was reduced by 54.74%w/v in comparison with the model group. CONCLUSION: MYR liposomes exhibited pH sensitivity and could potentially enhance the oral bioavailability and anti-hyperuricemic efficacy of MYR.

Comparative Analysis of Fluorescence Emission in Myricetin, Kaempferol, and Quercetin Powders and Solutions.

Myricetin is a flavonol with high antioxidant properties. In this research, the fluorescence emission of myricetin powder and its solutions in different solvents were measured and analyzed by comparing with the results of calculations. Comparison of the calculated and measured characteristic wavelengths allowed the identification of all the spectral features in the fluorescence spectra of myricetin powder and solutions with different concentrations. The computation was based on modeling the process of the excited state intermolecular proton transfer, which predicts the formation of tautomeric forms of the flavonol molecule. Characteristic emission wavelengths were obtained using TDDFT/M06-2X/6-31++G(d,p). To understand the influence of the hydroxyl groups in the B-ring of the flavonol molecule on the emission spectrum, we also compared the fluorescence spectra of myricetin with those of kaempferol and quercetin. Moreover, based on the analysis of the changes in the shape of the FL spectra with the concentration of the solution, a criterion for the complete dissolution of the flavonol powders was established, which is important for bioavailability of flavonoids.

Myricetin Acts as an Inhibitor of Type II NADH Dehydrogenase from Staphylococcus aureus.

BACKGROUND: Staphylococcus aureus is a common pathogenic microorganism in humans and animals. Type II NADH oxidoreductase (NDH-2) is the only NADH:quinone oxidoreductase present in this organism and represents a promising target for the development of anti-staphylococcal drugs. Recently, myricetin, a natural flavonoid from vegetables and fruits, was found to be a potential inhibitor of NDH-2 of S. aureus. The objective of this study was to evaluate the inhibitory properties of myricetin against NDH-2 and its impact on the growth and expression of virulence factors in S. aureus. RESULTS: A screening method was established to identify effective inhibitors of NDH-2, based on heterologously expressed S. aureus NDH-2. Myricetin was found to be an effective inhibitor of NDH-2 with a half maximal inhibitory concentration (IC50) of 2 µM. In silico predictions and enzyme inhibition kinetics further characterized myricetin as a competitive inhibitor of NDH-2 with respect to the substrate menadione (MK). The minimum inhibitory concentrations (MICs) of myricetin against S. aureus strains ranged from 64 to 128 µg/mL. Time-kill assays showed that myricetin was a bactericidal agent against S. aureus. In line with being a competitive inhibitor of the NDH-2 substrate MK, the anti-staphylococcal activity of myricetin was antagonized by MK-4. In addition, myricetin was found to inhibit the gene expression of enterotoxin SeA and reduce the hemolytic activity induced by S. aureus culture on rabbit erythrocytes in a dose-dependent manner. CONCLUSIONS: Myricetin was newly discovered to be a competitive inhibitor of S. aureus NDH-2 in relation to the substrate MK. This discovery offers a fresh perspective on the anti-staphylococcal activity of myricetin.

Myricetin Amorphous Solid Dispersions-Antineurodegenerative Potential.

Our research aimed to develop an amorphous solid dispersion (ASD) of myricetin (MYR) with Polyvinylpyrrolidone K30 (PVP30) to enhance its solubility, dissolution rate, antioxidant, and neuroprotective properties. Employing a combination of solvent evaporation and freeze drying, we successfully formed MYR ASDs. XRPD analysis confirmed complete amorphization in 1:8 and 1:9 MYR-PVP weight ratios. DSC thermograms exhibited a single glass transition (Tg), indicating full miscibility. FT-IR results and molecular modeling confirmed hydrogen bonds stabilizing MYR's amorphous state. HPLC analysis indicated the absence of degradation products, ensuring safe MYR delivery systems. Solubility, dissolution rate (pH 1.2 and 6.8), antioxidant (ABTS, DPPH, CUPRAC, and FRAP assays), and in vitro neuroprotective activities (inhibition of cholinesterases: AChE and BChE) were significantly improved compared to the pure compound. Molecular docking studies revealed that MYR had made several hydrogen, hydrophobic, and π-π stacking interactions, which could explain the compound's potency to inhibit AChE and BChE. MYR-PVP 1:9 w/w ASD has the best solubility, antioxidant, and neuroprotective activity. Stability studies confirmed the physical stability of MYR-PVP 1:9 w/w ASD immediately after dissolution and for two months under ambient conditions. Our study showed that the obtained ASDs are promising systems for the delivery of MYR with the potential for use in alleviating the symptoms of neurodegenerative diseases.

Antimicrobial potential of myricetin-coated zinc oxide nanocomposite against drug-resistant Clostridium perfringens.

BACKGROUND: Clostridium perfringens (C. perfringens) is an important pathogen in livestock animals and humans causing a wide array of systemic and enteric diseases. The current study was performed to investigate the inhibitory activity of myricetin (MYR), polyvinyl alcohol (PVA), and zinc oxide (ZnO) nanocomposite against growth and α-hemolysin of C. perfringens isolated from beef meat and chicken sources. RESULTS: The overall occurrence of C. perfringens was 29.8%. The prevalence of C. perfringens was higher in chicken (38.3%) than in beef meat products (10%). The antimicrobial susceptibility testing revealed that C. perfringens isolates exhibited high resistance levels for metronidazole (93%), bacitracin (89%), penicillin G (84%), and lincomycin (76%). Of note, 1% of C. perfringens isolates were pandrug-resistant (PDR), 4% were extensive drug-resistant (XDR), while 91% were multidrug-resistant. The results of broth microdilution technique revealed that all tested C. perfringens isolates were susceptible to MYR-loaded ZnO/PVA with minimum inhibitory concentrations (MICs) ranged from 0.125 to 2 µg/mL. Moreover, the MYR either alone or combined with the nanocomposite had no cytotoxic activities on chicken red blood cells (cRBCs). Transcriptional modifications of MYR, ZnO, ZnO/PVA, and ZnO/PVA/MYR nanocomposite were determined, and the results showed significant down-regulation of α-hemolysin fold change to 0.5, 0.7, 0.6, and 0.28, respectively compared to the untreated bacteria. CONCLUSION: This is an in vitro study reporting the antimicrobial potential of MYR-coated ZnO nanocomposite as an effective therapeutic candidate against C. perfringens. An in vivo approach is the next step to provide evidence for applying these alternatives in the treatment and prevention of C. perfringens-associated diseases.

Myricetin exerts anti-biofilm activity and attenuates osteomyelitis by inhibiting the TLR2/MAPK pathway in experimental mice.

AIMS: To evaluate the potential of Myricetin against S.aureus induced osteomyelitis. BACKGROUND: Osteomyelitis is infected condition of bone by micro-organisms. The mitogen-activated protein kinase (MAPK), inflammatory cytokines and Toll-like receptor-2 (TLR-2) pathway are mainly involved in osteomyelitis. Myricetin is a plant-food derived flavonoid which shows anti-inflammatory activity. OBJECTIVE: In the present study, we evaluated the potential of Myricetin against S.aureus induced osteomyelitis. MC3T3-E1 cells were used for in vitro studies. METHOD: Murine model of osteomyelitis was developed in BALB/c mice by injecting S.aureus in the medullary cavity of the femur. The mice were studied for bone destruction, anti-biofilm activity, osteoblast growth markers alkaline phosphatase (ALP), osteopontin (OCN) and collagen type-I (COLL-1) were studied by RT-PCR, ELISA analysis for levels of proinflammatory factors CRP, IL-6 and IL-1ß. Expression of proteins by Western blot analysis and anti-biofilm effect by Sytox green dye fluorescence assay. Target confirmation was done by performing in silico docking analysis. RESULTS: Myricetin reduced bone destruction in osteomyelitis induced mice. The treatment decreased bone levels of ALP, OCN, COLL-1 and TLR2. Myricetin decreased serum levels of CRP, IL-6 and IL-1ß. The treatment suppressed activation of MAPK pathway and showed anti-biofilm effect. Docking studies suggested high binding affinity of Myricetin with MAPK protein in silico, by showing lower binding energies. CONCLUSION: Myricetin suppresses osteomyelitis by inhibiting ALP, OCN, COLL-1 via the TLR2 and MAPK pathway involving inhibition of biofilm formation. In silico studies suggested MAPK as potential binding protein for myricetin.

Kinetics of Flavonoid Degradation and Controlled Release from Functionalized Magnetic Nanoparticles.

Flavonoids are naturally occurring antioxidants that have been shown to protect cell membranes from oxidative stress and have a potential use in photodynamic cancer treatment. However, they degrade at physiological pH values, which is often neglected in drug release studies. Kinetic study of flavonoid oxidation can help to understand the mechanism of degradation and to correctly analyze flavonoid release data. Additionally, the incorporation of flavonoids into magnetic nanocarriers can be utilized to mitigate degradation and overcome their low solubility, while the release can be controlled using magnetic fields (MFs). An approach that combines alternating least squares (ALS) and multilinear regression to consider flavonoid autoxidation in release studies is presented. This approach can be used in general cases to account for the degradation of unstable drugs released from nanoparticles. The oxidation of quercetin, myricetin (MCE), and myricitrin (MCI) was studied in PBS buffer (pH = 7.4) using UV-vis spectrophotometry. ALS was used to determine the kinetic profiles and characteristic spectra, which were used to analyze UV-vis data of release from functionalized magnetic nanoparticles (MNPs). MNPs were selected for their unique magnetic properties, which can be exploited for both targeted drug delivery and control over the drug release. MNPs were prepared and characterized by X-ray diffraction, infrared spectroscopy, scanning electron microscopy, superconducting quantum interference device magnetometer, and electrophoretic mobility measurements. Autoxidation of all three flavonoids follows a two-step first-order kinetic model. MCE showed the fastest degradation, while the oxidation of MCI was the slowest. The flavonoids were successfully loaded into the prepared MNPs, and the drug release was described by the first-order and Korsmeyer-Peppas models. External MFs were utilized to control the release mechanism and the cumulative mass of the flavonoids released.

Myricetin-Loaded Nanomicelles Protect against Cisplatin-Induced Acute Kidney Injury by Inhibiting the DNA Damage-cGAS-STING Signaling Pathway.

Acute kidney injury (AKI) is the most common side effect of the anti-cancer drug cisplatin, and currently, no effective preventive measures are available in clinical practice. Oxidative stress and DNA damage mechanisms may be involved in cisplatin-induced AKI. In this study, we prepared Kolliphor HS15-based myricetin-loaded (HS15-Myr) nanomicelles and explored the mechanism of protection against cisplatin-induced AKI. In vitro results showed that the HS15-Myr nanomicelles enhanced the antioxidant activity of myricetin (Myr) and inhibited cisplatin-induced proliferation inhibition of HK-2 cells. Moreover, the HS15-Myr nanomicelles inhibited cisplatin-induced reactive oxygen species accumulation, mitochondrial membrane potential reduction, and DNA damage, which might be related to the inhibition of the cyclic GMP-AMP synthase (cGAS)─stimulating interferon gene (STING) signaling pathway. In vivo results in mice showed that the significant reductions in body weight and renal indices and the increased blood urea nitrogen and serum creatinine levels induced by cisplatin could be significantly reversed by pretreating with the HS15-Myr nanomicelles. Furthermore, nanomicelle pretreatment significantly altered the activities of antioxidant enzymes (e.g., GSH, MDA, and SOD) induced by cisplatin. In addition, cisplatin-induced inflammatory responses in mouse kidney tissue were found to be inhibited by pretreatment with HS15-Myr nanomicelles, such as IL-1ß and TNF-α expression. The nanomicelles also significantly inhibited cisplatin-induced activation of the DNA damage-cGAS-STING pathway in kidney tissues. Together, our findings suggest that Myr-loaded nanomicelles are potential nephroprotective drugs.

Therapeutic role of kaempferol and myricetin in streptozotocin-induced diabetes synergistically via modulation in pancreatic amylase, glycogen storage and insulin secretion.

Kaempferol and Myricetin alone have promising benefits on diabetes and related complications, yet the effectiveness of cotreating the two compounds on diabetes have not been studied. The existing investigation was to study the combined anti-diabetic effect of kaempferol and myricetin in Streptozotocin (STZ)-activated diabetes in rats. To evaluate the anti-diabetic activity, 36 Wistar rats were segregated into six groups; Normal, 50 mg/kg STZ-induced diabetes, and four (50 mg/kg kaempferol, 50 mg/kg myricetin, 25 mg/kg kaempferol + myricetin, and 5 mg/kg glibenclamide) compound-treated diabetic groups. The effects of co-treatment on parameters, glucose, insulin, lipid profile, liver enzymes, antioxidant biomarkers, and inflammatory cytokines were measured. The study revealed that combined treatment restored the assessed parameters including glucose levels, inflammatory cytokines, oxidative markers, and lipid and liver enzymes in diabetic rats. The results indicate that cotreatment of kaempferol and myricetin has a beneficial role against diabetes suggesting that cotreatment of these compounds can be used therapeutically in treating diabetes.

Mur ligase F as a new target for the flavonoids quercitrin, myricetin, and (-)-epicatechin.

MurC, D, E, and F are ATP-dependent ligases involved in the stepwise assembly of the tetrapeptide stem of forming peptidoglycan. As highly conserved targets found exclusively in bacterial cells, they are of significant interest for antibacterial drug discovery. In this study, we employed a computer-aided molecular design approach to identify potential inhibitors of MurF. A biochemical inhibition assay was conducted, screening twenty-four flavonoids and related compounds against MurC-F, resulting in the identification of quercitrin, myricetin, and (-)-epicatechin as MurF inhibitors with IC50 values of 143 µM, 139 µM, and 92 µM, respectively. Notably, (-)-epicatechin demonstrated mixed type inhibition with ATP and uncompetitive inhibition with D-Ala-D-Ala dipeptide and UM3DAP substrates. Furthermore, in silico analysis using Sitemap and subsequent docking analysis using Glide revealed two plausible binding sites for (-)-epicatechin. The study also investigated the crucial structural features required for activity, with a particular focus on the substitution pattern and hydroxyl group positions, which were found to be important for the activity. The study highlights the significance of computational approaches in targeting essential enzymes involved in bacterial peptidoglycan synthesis.