Myricetin

1 Arctostaphylos sp. 2 Calluna sp. 3 Castanea sp. 4 Ceratonia sp. 5 Cochlospermum sp. 6 Drosera sp. 7 Epilobium sp. 8 Erica sp. 9 Eucalyptus sp. 10 Eugenia sp. 11 Euphorbia sp. 12 Fagus sp. 13 Galium sp. 14 Geranium sp. 15 Haematoxylum sp. 16 Hamamelis sp. 17 Hydrophyllum sp. 18 Hypericum sp. 19 Kadsura sp. 20 Liquidambar sp. 21 Lysimachia sp. 22 Melaleuca sp. 23 Myrtus sp. 24 Picea sp. 25 Pinus sp. 26 Pistacia sp. 27 Platanus sp. 28 Potentilla sp. 29 Primula sp. 30 Rhododendron sp. 31 Rhus sp. 32 Ribes sp. 33 Schinus sp. 34 Syzygium sp. 35 Thuja sp. 36 Vaccinium sp. 37 Vincetoxicum sp.

Myricetin is a common plant-derived flavonoid with a wide range of activities including strong anti-oxidant, anticancer, antidiabetic and anti-inflammatory activities.

In Vitro:Myricetin exhibits the scavenging activity towards a number of radicals and ions. It displays poor activity (IC50 value=1.4 mg/mL) in a superoxide dismutase (SOD)-like activity assay[1]. It prevents cancer cell death via apoptosis via regulation of PI3K/Akt and MAPK signalling pathways[2]. Myricetin exhibits antiphotoaging effects by quenching causative free radicals in the skin. Myricetin is able to suppress UVB-induced COX-2 expression in mouse skin epidermal JB6 P+ cells. It inhibits UVB-induced initiation of activator protein-1 and NF-κβ, as well as Fyn kinase activity[1]. Myricetin inhibits viability of SKOV3 ovarian cancer cells in a dose-dependent manner. It induces DNA DSBs and ER stress, which leads to apoptosis in SKOV3 cells[3]. Myricetin inhibits human Hsp70 by more than 80% with IC50 values of 83, 11 and 12 μM, respectively[4].

In Vivo:Treatment of orthotopic pancreatic tumors with myricetin results in tumor regression and decreases metastatic spread[2]. Exposure to 150 μM myricetin causes 14%, 26%, 5% and 49% inhibition of rabbit platelet aggregation, induced by ADP, arachidonic acid, collagen and PAF, respectively[5].

References:
[1]. Semwal DK, et al. Myricetin: A Dietary Molecule with Diverse Biological Activities. Nutrients. 2016 Feb 16;8(2):90. [2]. Phillips PA, et al. Myricetin induces pancreatic cancer cell death via the induction of apoptosis and inhibition of thephosphatidylinositol 3-kinase (PI3K) signaling pathway. Cancer Lett. 2011 Sep 28;308(2):181-8. [3]. Xu Y, et al. Myricetin induces apoptosis via endoplasmic reticulum stress and DNA double-strand breaks in human ovarian cancer cells. Mol Med Rep. 2016 Mar;13(3):2094-100. [4]. Jinwal UK, et al. Chemical Manipulation of Hsp70 ATPase Activity Regulates Tau Stability. J Neurosci. 2009 Sep 30;29(39):12079-88. [5]. Tzeng SH, et al. Inhibition of platelet aggregation by some flavonoids. Thromb Res. 1991 Oct 1;64(1):91-100.

Myricetin, quercetin and catechin-gallate inhibit glucose uptake in isolated rat adipocytes.[Pubmed:15469417]

Biochem J. 2005 Mar 15;386(Pt 3):471-8.

The facilitative glucose transporter, GLUT4, mediates insulin-stimulated glucose uptake in adipocytes and muscles, and the participation of GLUT4 in the pathogenesis of various clinical conditions associated with obesity, visceral fat accumulation and insulin resistance has been proposed. Glucose uptake by some members of the GLUT family, mainly GLUT1, is inhibited by flavonoids, the natural polyphenols present in fruits, vegetables and wine. Therefore it is of interest to establish if these polyphenolic compounds present in the diet, known to be effective antioxidants but also endowed with several other biological activities such as protein-tyrosine kinase inhibition, interfere with GLUT4 function. In the present study, we show that three flavonoids, quercetin, Myricetin and catechin-gallate, inhibit the uptake of methylglucose by adipocytes over the concentration range of 10-100 microM. These three flavonoids show a competitive pattern of inhibition, with K(i)=16, 33.5 and 90 microM respectively. In contrast, neither catechin nor gallic acid inhibit methylglucose uptake. To obtain a better understanding of the interaction among GLUT4 and flavonoids, we have derived a GLUT4 three-dimensional molecular comparative model, using structural co-ordinates from a GLUT3 comparative model and a mechanosensitive ion channel [PDB (Protein Data Bank) code 1MSL] solved by X-ray diffraction. On the whole, the experimental evidence and computer simulation data favour a transport inhibition mechanism in which flavonoids and GLUT4 interact directly, rather than by a mechanism related to protein-tyrosine kinase and insulin signalling inhibition. Furthermore, the results suggest that GLUT transporters are involved in flavonoid incorporation into cells.

Myricetin prevents titanium particle-induced osteolysis in vivo and inhibits RANKL-induced osteoclastogenesis in vitro.[Pubmed:25449599]

Biochem Pharmacol. 2015 Jan 1;93(1):59-71.

Titanium (Ti) particle-induced periprosthetic osteolysis and subsequent aseptic loosening are a primary reason for total hip arthroplasty failure. The aim of this study was to assess the effect of Myricetin on Ti particle-induced osteolysis and osteoclastogenesis. We demonstrated that Myricetin, a natural plant extract, exerts potent inhibitory effects on Ti particle-induced osteolysis in a mouse calvarial model. Further histological analysis indicated that the inhibition of osteoclast formation and function, and the secretion of inflammatory factors, are key targets for therapeutic agents in the treatment of wear particle-induced osteolysis. In vitro, we found that Myricetin suppressed receptor activator of nuclear factor-kappaB ligand (RANKL)-mediated osteoclast differentiation, bone resorption, and F-actin ring formation in a dose-dependent manner. Moreover, Myricetin significantly reduced the expression of osteoclast-specific markers in mouse bone marrow-derived macrophages, including tartrate-resistant acid phosphatase (TRAP), cathepsin K, the calcitonin receptor, V-ATPase d2, c-fos, and nuclear factor of activated T cells (NFAT) c1. Further investigation revealed that Myricetin inhibited osteoclastogenesis through the suppression of the nuclear factor-kappaB (NF-kappaB) signaling pathway and mitogen-activated protein kinase (MAPK) pathways involving extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase 1/2 (JNK1/2). While, the inhibition of TNF-alpha and IL-1beta secretion was another reason for the suppressive effect of Myricetin on Ti particle-induced osteolysis. Collectively, these findings suggest that Myricetin is a potential natural agent for the treatment of periprosthetic osteolysis and other osteoclast-related osteolytic diseases.

Myricetin suppresses UVB-induced wrinkle formation and MMP-9 expression by inhibiting Raf.[Pubmed:20093107]

Biochem Pharmacol. 2010 May 15;79(10):1455-61.

Chronic exposure to solar ultraviolet (UV) light causes skin photoaging. Many studies have shown that naturally occurring phytochemicals have anti-photoaging effects, but their direct target molecule(s) and mechanism(s) remain unclear. We found that Myricetin, a major flavonoid in berries and red wine, inhibited wrinkle formation in mouse skin induced by chronic UVB irradiation (0.18J/cm(2), 3 days/week for 15 weeks). Myricetin treatment reduced UVB-induced epidermal thickening of mouse skin and also suppressed UVB-induced matrix metalloproteinase-9 (MMP-9) protein expression and enzyme activity. Myricetin appeared to exert its anti-aging effects by suppressing UVB-induced Raf kinase activity and subsequent attenuation of UVB-induced phosphorylation of MEK and ERK in mouse skin. In vitro and in vivo pull-down assays revealed that Myricetin bound with Raf in an ATP-noncompetitive manner. Overall, these results indicate that Myricetin exerts potent anti-photoaging activity by regulating MMP-9 expression through the suppression of Raf kinase activity.

Myricetin inhibits the release of glutamate in rat cerebrocortical nerve terminals.[Pubmed:25340625]

J Med Food. 2015 May;18(5):516-23.

The excessive release of glutamate is a critical element in the neuropathology of acute and chronic brain disorders. The purpose of the present study was to investigate the effect and possible mechanism of Myricetin, a naturally occurring flavonoid with a neuroprotective profile, on endogenous glutamate release in the nerve terminals (synaptosomes) of the rat cerebral cortex. The release of glutamate was evoked by the K(+) channel blocker 4-aminopyridine (4-AP) and measured by one-line enzyme-coupled fluorometric assay. We also used a membrane potential-sensitive dye to assay the synaptosomal plasma membrane potential, and a Ca(2+) indicator Fura-2 to monitor cytosolic Ca(2+) concentrations ([Ca(2+)]C). Results show that Myricetin inhibited 4-AP-evoked glutamate release, and this effect was prevented by chelating extracellular Ca(2+) ions and the vesicular transporter inhibitor bafilomycin A1. However, the glutamate transporter inhibitor dl-threo-beta-benzyl-oxyaspartate had no effect on Myricetin action. Myricetin did not alter the synaptosomal membrane potential, but decreased 4-AP-induced increases in the cytosolic free Ca(2+) concentration. Furthermore, the Myricetin effect on 4-AP-evoked glutamate release was prevented by blocking the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels, but not by blocking intracellular Ca(2+) release. These results suggest that Myricetin inhibits glutamate release from cerebrocortical synaptosomes by attenuating voltage-dependent Ca(2+) entry. This implies that the inhibition of glutamate release is an important pharmacological activity of Myricetin that may play a critical role in the apparent clinical efficacy of this compound.

Myricetin prevents fibrillogenesis of hen egg white lysozyme.[Pubmed:25196984]

J Agric Food Chem. 2014 Oct 1;62(39):9442-9.

Myricetin is a natural flavonol found in many grapes, berries, fruits, vegetables, and herbs as well as other plants. Recent studies have identified potential antiamyloidogenic activity for this compound. In this study, the kinetics of amyloid fibril formation by hen egg white lysozyme (HEWL) and the antifibril-forming activity of Myricetin were investigated. We demonstrate that Myricetin significantly inhibits the fibrillation of HEWL and the inhibitory effect is dose-dependent. Interestingly, the inhibitory effect toward HEWL fibrillation was stronger than that exerted by the previously characterized fibril-forming inhibitor quercetin, which has high structural similarity with Myricetin. Spectrofluorometric and computational studies suggest that the mechanism underlying the inhibitory action of Myricetin at a molecular level is to reduce the population of partially unfolded HEWL intermediates. This action is achieved by the tight binding of Myricetin to the aggregation-prone region of the beta-domain of HEWL and linking to the relatively stable alpha-domain, thus resulting in the inhibition of amyloid fibril formation.

Myricetin exerts anti-proliferative, anti-invasive, and pro-apoptotic effects on esophageal carcinoma EC9706 and KYSE30 cells via RSK2.[Pubmed:25192723]

Tumour Biol. 2014 Dec;35(12):12583-92.

Myricetin, a common dietary flavonoid, is widely distributed in fruits and vegetables and is used as a health food supplement based on its anti-tumor properties. However, the effect and mechanisms of Myricetin in esophageal carcinoma are not fully understood. Here, we demonstrated the effect of Myricetin on the proliferation, apoptosis, and invasion of the esophageal carcinoma cell lines EC9706 and KYSE30 and explored the underlying mechanism and target protein(s) of Myricetin. CCK-8 assay, transwell invasion assay, wound-healing assay, cell cycle analysis, and apoptosis assay were used to evaluate the effects of Myricetin on cell proliferation, invasion, and apoptosis. Nude mouse tumor xenograft model was built to understand the interaction between Myricetin and NTD RSK2. Pull-down assay was used to verify molecular mechanism. Myricetin inhibited proliferation and invasion and induced apoptosis of EC9706 and KYSE30 cells. Moreover, Myricetin was shown to bind RSK2 through the NH2-terminal kinase domain. Finally, Myricetin inhibited EC9706 and KYSE30 cell proliferation through Mad1 and induced cell apoptosis via Bad. Myricetin inhibits the proliferation and invasion and induces apoptosis in EC9706 and KYSE30 cells via RSK2. Myricetin exerts anti-proliferative, anti-invasive, and pro-apoptotic effects on esophageal carcinoma EC9706 and KYSE30 cells via RSK2. Our results provide novel insight into Myricetin as a potential agent for the prevention and treatment of esophageal carcinoma.

Myricetin enhances osteogenic differentiation through the activation of canonical Wnt/beta-catenin signaling in human bone marrow stromal cells.[Pubmed:24876056]

Eur J Pharmacol. 2014 Sep 5;738:22-30.

Myricetina flavonoid compound, has been reported to possess antioxidative, antiproliferative and anti-inflammatory effects. However, no study has yet investigated the effect of Myricetin on osteogenic differentiation of human bone marrow stem cells (hBMSCs). This study was designed to investigate the effects of Myricetin on osteogenic differentiation of hBMSCs in vitro. Cell viability was analyzed by MTT and osteogenic differentiation was evaluated by alkaline phosphatase (ALP) activity assay, Alizarin red S dye, real time-polymerase chain reaction (RT-PCR) and Western blot analysis. We found that the ALP activity and the mineralization of hBMSCs were enhanced by treatment with Myricetin. Myricetin increased the mRNA expressions of Osteocalcin (OCN), Collagen type I (COL-I), ALP and Runt-related transcription factor 2 (RUNX2). Additionally, we found that Myricetin activated the Wnt/beta-catenin pathway and increased the expression of several downstream genes including T-cell factor-1(TCF-1) and lymphoid enhancer factor-1 (LEF-1). Depletion of beta-catenin almost completely blocked the positive role of Myricetin on osteogenic differentiation. Taken together, our findings suggest that Myricetin enhanced osteogenic differentiation of hBMSCs by activating the Wnt/beta-catenin signaling. The study may aid in the development of a therapeutic approach utilizing Myricetin for the enhancement of bone health and prevention of osteoporosis.

Inhibitory effects of myricetin on mammalian DNA polymerase, topoisomerase and human cancer cell proliferation.[Pubmed:23561189]

Food Chem. 2013 Aug 15;139(1-4):910-8.

In this study, the inhibitory activities against mammalian DNA polymerases (pols) of 16 major bioflavonoids were investigated. Myricetin (3,3',4',5,5',7-hexahydroxyflavone) was the most potent inhibitor of pols amongst the compounds tested, with IC50 values of 21.3-40.9 muM. This compound did not affect the activities of plant (cauliflower) pol alpha or prokaryotic pols. Myricetin also inhibited human DNA topoisomerase II (topo II) activity with an IC50 value of 27.5 muM, but did not inhibit the activities of other DNA metabolic enzymes tested. Myricetin also did not influence the direct binding to double stranded DNA as determined by thermal transition analysis. It was found to prevent the proliferation of human colon HCT116 carcinoma cells with an LD50 of 28.2 muM, halt the cell cycle in G2/M phase, and induce apoptosis. These results suggest that the decrease of proliferation may be a result of the inhibition of cellular topoisomerase (topo) II rather than pols.

Myricetin, a natural flavonoid with antioxidant and anti tumor properties, is a novel inhibitor of MEK1 activity and transformation of JB6 P+ mouse epidermal cells. It also inhibits PI3Kγ with Kd of 0.17 μM.

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