MEK1; PI3Kγ (Kd = 0.17 μM)

杨梅素（Cannabiscetin）是一种具有抗氧化和抗肿瘤特性的黄酮类化合物，存在于多种植物中，包括葡萄、浆果、水果、蔬菜、草药和其他植物。杨梅素的抗氧化特性。根据体外研究，高浓度的杨梅素可能会改变低密度脂蛋白胆固醇，从而增加白细胞的摄取。 [1] 根据研究，高杨梅素摄入量可降低患胰腺癌和前列腺癌的风险。 [2] [3]

用杨梅素处理的原位肿瘤激酶表现出消退和增殖减少[2]。在接受 150 μM 杨梅素处理的兔子中，发现 ADP、花生四烯酸、胶原蛋白、PAF 以及 14%、26%、5% 和 49% 的兔子分别出现局部肿瘤 [5]。

杨梅素 (12.5-200 μM) 用于治疗胰腺癌细胞（MIA PaCa-2、Panc-1 或 S2-013）或健康胰腺导管细胞 (PDC)。 Dojindo Cell Counting Kit-8 用于评估细胞活力。将 1×104 个细胞接种到 96 孔板的每个孔中，让细胞贴壁过夜。在给予不同浓度的杨梅素处理24小时后，将10微升四唑底物添加到板的每个孔中。板在 37°C 孵育一小时后测量 450 nm 处的吸光度。

Mice: For 35 days (MIA PaCa-2 model) or 18 days (S2-013 model), mice receive daily intraperitoneal injections of myricetin (30 mg/kg in the MIA PaCa-2 model and 50 mg/kg in the S2-013 model) or a vehicle (DMSO). To track tumor growth, ultrasound measurements are taken on a regular basis. At the conclusion of the in vivo experiment, the tumor volume and size are calculated[2].

Absorption, Distribution and Excretion
... Significant quantities of quercetin and possibly myricetin and kaempferol are absorbed in the gut. A larger fraction probably remains in the lumen, and thus a substantial proportion of the gastrointestinal mucosa is exposed to biologically significant concentrations of these compounds. ...

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Metabolism / Metabolites
Myricetin has known human metabolites that include (2S,3S,4S,5R)-6-[5,7-Dihydroxy-4-oxo-2-(3,4,5-trihydroxyphenyl)chromen-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid.

Interactions
... Addition of apigenin, chrysin, fisetin, flavonone, galangin, hesperitin, kaempferol, morin, myricetin, haringenin, or quercetin to human liver microsomes inhibited the hydroxylation of benzo(a)pyrene. In contrast to these results, the addition of flavone, nobiletin, tangeretin, or 7,8-benzoflavone to human liver microsomes caused a many-fold stimulation in the hydroxylation of benzo(a)pyrene, the metabolism of aflatoxin B1 to 2,3-dihydro-2,3-dihydroxyaflatoxin B1, and the metabolic activation of aflatoxin B1 to mutagenic products. ... An examination of the structural features required for the inhibition and stimulation of benzo(a)pyrene hydroxylation indicated that all of the 12 flavonoid inhibitors that were studied possessed hydroxyl groups whereas the flavonoid activators were less polar molecules that lacked hydroxyl groups.
... Myricetin suppresses UVB-induced cyclooxygenase-2 (COX-2) expression in mouse skin epidermal JB6 P+ cells. The activation of activator protein-1 and nuclear factor-kappaB induced by UVB was dose-dependently inhibited by myricetin treatment. Western blot and kinase assay data revealed that myricetin inhibited Fyn kinase activity and subsequently attenuated UVB-induced phosphorylation of mitogen-activated protein kinases. Pull-down assays revealed that myricetin competitively bound with ATP to suppress Fyn kinase activity. Importantly, myricetin exerted similar inhibitory effects compared with 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, a well-known pharmacologic inhibitor of Fyn. In vivo mouse skin data also revealed that myricetin inhibited Fyn kinase activity directly and subsequently attenuated UVB-induced COX-2 expression. Mouse skin tumorigenesis data clearly showed that pretreatment with myricetin significantly suppressed UVB-induced skin tumor incidence in a dose-dependent manner. Docking data suggest that myricetin is easily docked to the ATP-binding site of Fyn, which is located between the N and C lobes of the kinase domain. Overall, these results indicated that myricetin exerts potent chemopreventive activity mainly by targeting Fyn in skin carcinogenesis.
... Bor-tezomib is a dipeptide boronate proteasome inhibitor that has activity in the treatment of multiple myeloma but is not effective in chronic lymphocytic leukemia (CLL). Although CLL cells are sensitive in vitro to bortezomib-induced apoptosis when cultured in medium, the killing activity was blocked when cultured in 50% fresh autologous plasma. Dietary flavonoids, quercetin and myricetin, which are abundant in plasma, inhibited bortezomib-induced apoptosis of primary CLL and malignant B-cell lines in a dose-dependent manner...
The purpose of this study was to investigate the potential neuroprotective effects of myricetin (flavonoid) and fraxetin (coumarin) on rotenone-induced apoptosis in SH-SY5Y cells, and the possible signal pathway involved in a neuronal cell model of Parkinson's disease. ... Rotenone caused a time- and dose-dependent decrease in cell viability and the degree of LDH release was proportionally to the effects on cell viability. Cells were pretreated with fraxetin, myricetin and N-acetylcysteine at different concentrations for 30 min before exposure to rotenone. Cytotoxicity of rotenone (5 uM) for 16 hr was significantly diminished as well as the release of LDH into the medium, by the effect of fraxetin, myricetin and N-acetylcysteine, with fraxetin (100 uM) and N-acetylcysteine (100 uM) being more effective than myricetin (50 uM)...
The effects of myricetin on either MRP1 or MRP2 mediated vincristine resistance in transfected MDCKII cells were examined. The results obtained show that myricetin can inhibit both MRP1 and MRP2 mediated vincristine efflux in a concentration dependent manner. The IC50 values for cellular vincristine transport inhibition by myricetin were 30.5+/-1.7 uM for MRP1 and 24.6+/-1.3 uM for MRP2 containing MDCKII cells. Cell proliferation analysis showed that the MDCKII control cells are very sensitive towards vincristine toxicity with an IC50 value of 1.1+/-0.1 uM. The MDCKII MRP1 and MRP2 cells are less sensitive towards vincristine toxicity with IC50 values of 33.1+/-1.9 and 22.2+/-1.4 uM, respectively. In both the MRP1 and MRP2 cells, exposure to 25 uM myricetin enhances the sensitivity of the cells towards vincristine toxicity to IC50 values of 7.6+/-0.5 and 5.8+/-0.5 uM, respectively. The increase of sensitivity represents a reversal of the resistance towards vincristine as a result of MRP1 and MRP2 inhibition...

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Non-Human Toxicity Values
LD50 Mouse intraperitoneal 1410 mg/kg

[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 is a hexahydroxyflavone that is flavone substituted by hydroxy groups at positions 3, 3', 4', 5, 5' and 7. It has been isolated from the leaves of Myrica rubra and other plants. It has a role as a cyclooxygenase 1 inhibitor, an antineoplastic agent, an antioxidant, a plant metabolite, a food component, a hypoglycemic agent and a geroprotector. It is a hexahydroxyflavone and a 7-hydroxyflavonol. It is a conjugate acid of a myricetin(1-).
Myricetin has been reported in Caragana frutex, Camellia sinensis, and other organisms with data available.
Myricetin is a metabolite found in or produced by Saccharomyces cerevisiae.
See also: Quercetin (subclass of).

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Mechanism of Action
Dietary polyphenols are a diverse and complex group of compounds that are linked to human health. Many of their effects have been attributed to the ability to poison (i.e., enhance DNA cleavage by) topoisomerase II. Polyphenols act against the enzyme by at least two different mechanisms. Some compounds are traditional, redox-independent topoisomerase II poisons, interacting with the enzyme in a noncovalent manner. Conversely, others enhance DNA cleavage in a redox-dependent manner that requires covalent adduction to topoisomerase II. Unfortunately, the structural elements that dictate the mechanism by which polyphenols poison topoisomerase II have not been identified. To resolve this issue, the activities of two classes of polyphenols against human topoisomerase IIalpha were examined. The first class was a catechin series, including (-)-epigallocatechin gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epicatechin (EC). The second was a flavonol series, including myricetin, quercetin, and kaempferol. Compounds were categorized into four distinct groups: EGCG and EGC were redox-dependent topoisomerase II poisons, kaempferol and quercetin were traditional poisons, myricetin utilized both mechanisms, and ECG and EC displayed no significant activity. On the basis of these findings, a set of rules is proposed that predicts the mechanism of bioflavonoid action against topoisomerase II. The first rule centers on the B ring. While the C4'-OH is critical for the compound to act as a traditional poison, the addition of -OH groups at C3' and C5' increases the redox activity of the B ring and allows the compound to act as a redox-dependent poison. The second rule centers on the C ring. The structure of the C ring in the flavonols is aromatic and planar and includes a C4-keto group that allows the formation of a proposed pseudo ring with the C5-OH. Disruption of these elements abrogates enzyme binding and precludes the ability to function as a traditional topoisomerase II poison.
Selected flavonoids were tested for their ability to inhibit the catalytic activity of DNA topoisomerase (topo) I and II. Myricetin, quercetin, fisetin, and morin were found to inhibit both enzymes, while phloretin, kaempferol, and 4',6,7-trihydroxyisoflavone inhibited topo II without inhibiting topo I. Flavonoids demonstrating potent topo I and II inhibition required hydroxyl group substitution at the C-3, C-7, C-3', and C-4' positions and also required a keto group at C-4. Additional B-ring hydroxylation enhanced flavonoid topo I inhibitory action. A C-2, C-3 double bond was also required, but when the A ring is opened, the requirement for the double bond was eliminated. Genistein has been previously reported to stabilize the covalent topo II-DNA cleavage complex and thus function as a topo II poison. All flavonoids were tested for their ability to stabilize the cleavage complex between topo I or topo II and DNA. None of the agents stabilized the topo I-DNA cleavage complex, but prunetin, quercetin, kaempferol, and apigenin stabilized the topo II DNA-complex. Competition experiments have shown that genistein-induced topo II-mediated DNA cleavage can be inhibited by myricetin, suggesting that both types of inhibitors (antagonists and poisons) interact with the same functional domain of their target enzyme...
... myricetin (3, 3', 4', 5, 5', 7-hexahydroxyflavone) ... could directly bind to JAK1/STAT3 molecules to inhibit cell transformation in epidermal growth factor (EGF)-activated mouse JB6 P(+) cells. Colony assay revealed that myricetin had the strongest inhibitory effect on cell transformation among three flavonols including myricetin, quercetin and kaempferol. Molecular data revealed that myricetin inhibited DNA- binding and transcriptional activity of STAT3. Furthermore, myricetin inhibited the phosphorylation of STAT3 at Tyr705 and Ser727. Cellular signaling analyses revealed that EGF could induce the phosphorylation of Janus Kinase (JAK) 1, but not JAK2. Myricetin inhibited the phosphorylation of JAK1 and increased the autophosphorylation of EGF receptor (EGFR). Moreover, ex vivo and in vitro pull-down assay revealed that myricetin bound to JAK1 and STAT3, but not EGFR. Affinity data further demonstrated that myricetin had a higher affinity for JAK1 than STAT3. Thus, ... myricetin might directly target JAK1 to block cell transformation in mouse JB6 cells.
Abnormal expression of cyclooxygenase-2 (COX-2) has been implicated in the development of cancer. ... Here /it is reported/ that 3,3',4',5,5',7-hexahydroxyflavone (myricetin), one of the major flavonols in red wine, inhibits 12-O-tetradecanoylphorbol-13-acetate (phorbol ester)-induced COX-2 expression in JB6 P+ mouse epidermal (JB6 P+) cells by suppressing activation of nuclear factor kappa B (NF-kappaB). Myricetin at 10 and 20 uM inhibited phorbol ester-induced upregulation of COX-2 protein, while resveratrol at the same concentration did not exert significant effects. The phorbol ester-induced production of prostaglandin E 2 was also attenuated by myricetin treatment. Myricetin inhibited both COX-2 and NF-kappaB transactivation in phorbol ester-treated JB6 P+ cells, as determined using a luciferase assay. Myricetin blocked the phorbol ester-stimulated DNA binding activity of NF-kappaB, as determined using an electrophoretic mobility shift assay. Moreover, TPCK (N-tosyl-l-phenylalanine chloromethyl ketone), a NF-kappaB inhibitor, significantly attenuated COX-2 expression and NF-kappaB promoter activity in phorbol ester-treated JB6 P+ cells. In addition, red wine extract inhibited phorbol ester-induced COX-2 expression and NF-kappaB transactivation in JB6 P+ cells. Collectively, these data suggest that myricetin contributes to the chemopreventive effects of red wine through inhibition of COX-2 expression by blocking the activation of NF-kappaB.
For more Mechanism of Action (Complete) data for MYRICETIN (6 total), please visit the HSDB record page.

C15H10O8

318.24

318.037

C, 56.61; H, 3.17; O, 40.22

529-44-2

Dihydromyricetin;27200-12-0;Myricetin-13C3

5281672

Yellow needles from dilute alcohol

1.9±0.1 g/cm3

747.6±60.0 °C at 760 mmHg

>300 °C(lit.)

285.9±26.4 °C

0.0±2.6 mmHg at 25°C

1.864

2.11

151.59

6

8

1

23

506

0

O1C2=C([H])C(=C([H])C(=C2C(C(=C1C1C([H])=C(C(=C(C=1[H])O[H])O[H])O[H])O[H])=O)O[H])O[H]

IKMDFBPHZNJCSN-UHFFFAOYSA-N

InChI=1S/C15H10O8/c16-6-3-7(17)11-10(4-6)23-15(14(22)13(11)21)5-1-8(18)12(20)9(19)2-5/h1-4,16-20,22H

3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)chromen-4-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.08 mg/mL (6.54 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (6.54 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: 4% DMSO +30%PEG 300 +ddH2O: 5mg/mL

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
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6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。