Mechanism Of Myricetin Research Articles

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-1β 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-1β-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 possesses the potency against SARS-CoV-2 infection through blocking viral-entry facilitators and suppressing inflammation in rats and mice

Myricetin (3,5,7-trihydroxy-2-(3,4,5-tri hydroxyphenyl)-4-benzopyrone) is a common flavonol extracted from many natural plants and Chinese herb medicines and has been demonstrated to have multiple pharmacological activities, such as anti-microbial, anti-thrombotic, neuroprotective, and anti-inflammatory effects. Previously, myricetin was reported to target Mpro and 3CL-Pro-enzymatic activity to SARS-CoV-2. However, the protective value of myricetin on SARS-Cov-2 infection through viral-entry facilitators has not yet been comprehensively understood. The aim of the current study was to evaluate the pharmacological efficacy and the mechanisms of action of myricetin against SARS-CoV-2 infection both in vitro and in vivo. The inhibitory effects of myricetin on SARS-CoV-2 infection and replication were assessed on Vero E6 cells. Molecular docking analysis and bilayer interferometry (BLI) assays, immunocytochemistry (ICC), and pseudoviruses assays were performed to evaluate the roles of myricetin in the intermolecular interaction between the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein and angiotensin-converting enzyme 2 (ACE2). The anti-inflammatory potency and mechanisms of myricetin were examined in THP1 macrophages in vitro, as well as in carrageenan-induced paw edema, delayed-type hypersensitivity (DTH) induced auricle edema, and LPS-induced acute lung injury (ALI) animal models. The results showed that myricetin was able to inhibit binding between the RBD of the SARS-CoV-2 S protein and ACE2 through molecular docking analysis and BLI assay, demonstrating its potential as a viral-entry facilitator blocker. Myricetin could also significantly inhibit SASR-CoV-2 infection and replication in Vero E6 cells (EC50 55.18μM), which was further validated with pseudoviruses containing the RBD (wild-type, N501Y, N439K, Y453F) and an S1 glycoprotein mutant (S-D614G). Moreover, myricetin exhibited a marked suppressive action on the receptor-interacting serine/threonine protein kinase 1 (RIPK1)-driven inflammation and NF-kappa B signaling in THP1 macrophages. In animal model studies, myricetin notably ameliorated carrageenan-induced paw edema in rats, DTH induced auricle edema in mice, and LPS-induced ALI in mice. Our findings showed that myricetin inhibited HCoV-229E and SARS-CoV-2 replication in vitro, blocked SARS-CoV-2 virus entry facilitators and relieved inflammation through the RIPK1/NF-κB pathway, suggesting that this flavonol has the potential to be developed as a therapeutic agent against COVID-19.

Myricetin is effective and selective in inhibiting imatinib-resistant chronic myeloid leukemia stem and differentiated cells through targeting eIF4E.

Although imatinib has revolutionized the treatment of chronic myeloid leukemia (CML), s develop resistance to imatinib when progress to blast phase and relapse. Myricetin, a flavonoid compound found in natural plants, has multiple biological functions. In this study, we show that myricetin demonstrated potent efficacy in imatinib-resistant CML CD34 + stem/progenitor cells with less toxicity in normal bone marrow. Myricetin is also active against imatinib-resistant CML bulk cells. The in vitro observations on the therapeutic effects of myricetin were translatable to in vivo imatinib-resistant CML xenograft mouse models. Mechanism studies showed that myricetin decreased the phosphorylation of eIF4E and Ak strain transforming, and the protein level of c-Myc and Cyclin D1. Rescue studies using eIF4E (S209D) and (S209A) confirmed that eIF4E phosphorylation inhibition was the mechanism of myricetin's action in CML. Our results suggest that myricetin may be a potential lead for drug development to overcome imatinib resistance in CML.

Myricetin inhibits interferon-γ-induced PD-L1 and IDO1 expression in lung cancer cells

Programmed death ligand-1 (PD-L1) and indoleamine 2, 3-dioxygenase 1 (IDO1) are immune checkpoints induced by interferon-γ (IFN-γ) in the tumor microenvironment, leading to immune escape of tumors. Myricetin (MY) is a flavonoid distributed in many edible and medicinal plants. In this study, MY was identified to inhibit IFN-γ-induced PD-L1 expression in human lung cancer cells. It also reduced the expression of IDO1 and the production of kynurenine which is the product catalyzed by IDO1, while didn’t show obvious effect on the expression of major histocompatibility complex-I (MHC-I), a crucial molecule for antigen presentation. In addition, the function of T cells was evaluated using a co-culture system consist of lung cancer cells and the Jurkat-PD-1 T cell line overexpressing PD-1. MY restored the survival, proliferation, CD69 expression and interleukin-2 (IL-2) secretion of Jurkat-PD-1 T cells suppressed by IFN-γ-treated lung cancer cells. Mechanistically, IFN-γ up-regulated PD-L1 and IDO1 at the transcriptional level through the JAK-STAT-IRF1 axis, which was targeted and inhibited by MY. Together, our research revealed a new mechanism of MY mediated anti-tumor activity and highlighted the potential implications of MY in tumor immunotherapy.

Myricetin suppresses the proliferation and migration of vascular smooth muscle cells and inhibits neointimal hyperplasia via suppressing TGFBR1 signaling pathways

BackgroundNeointimal formation, mediated by the proliferation and migration of vascular smooth muscle cells (VSMCs), is a common pathological basis for atherosclerosis and restenosis. Myricetin, a natural flavonoid, reportedly exerts anti-atherosclerotic effects. However, the effect and mechanism of myricetin on VSMCs proliferation and migration and neointimal hyperplasia (NIH) remain unknown. PurposeWe investigated myricetin's effect on NIH, as well as the potential involvement of transforming growth factor-beta receptor 1 (TGFBR1) signaling in mediating myricetin's anti-atherosclerotic and anti-restenotic actions. MethodsMyricetin's effects on the proliferation and migration of HASMCs and A7R5 cells were determined by CCK-8, EdU assays, wound healing, Transwell assays, and western blotting (WB).Molecular docking, molecular dynamics (MD) simulation, surface plasmon resonance (SPR) and TGFBR1 kinase activity assays were employed to investigate the interaction between myricetin and TGFBR1. An adenovirus vector encoding TGFBR1 was used to verify the effects of myricetin. In vivo, the left common carotid artery (LCCA) ligation mouse model was adopted to determine the impacts of myricetin on neointimal formation and TGFBR1 activation. ResultsMyricetin dose-dependently inhibited the migration and proliferation in VSMCs, suppressed the expression of CDK4, cyclin D3, MMP2, and MMP9. Molecular docking revealed that myricetin binds to key regions for TGFBR1 antagonist binding, and the binding energy was -9.61 kcal/mol. MD simulation indicated stable binding between TGFBR1 and myricetin. Additionally, SPR revealed an equilibrium dissociation constant of 4.35 × 10−5 M between myricetin and TGFBR1. According to the TGFBR1 kinase activity assay, myricetin directly inhibited TGFBR1 kinase activity (IC50 = 8.551 μM). Furthermore, myricetin suppressed the phosphorylation level of TGFBR1, Smad2, and Smad3 in a dose-dependent pattern, which was partially inhibited by TGFBR1 overexpression. Consistently, TGFBR1 overexpression partially rescued the suppressive roles of myricetin on VSMCs migration and proliferation. Moreover, myricetin dramatically inhibited NIH and reduced TGFBR1, Smad2, and Smad3 phosphorylation in the LCCA. ConclusionThis is the first study to demonstrate that myricetin suppresses NIH and VSMC proliferation and migration via inhibiting TGFBR1 signaling. Myricetin can be developed as a potential therapeutic candidate for treating atherosclerosis and vascular restenosis.

Myricetin ameliorates bleomycin-induced pulmonary fibrosis in mice by inhibiting TGF-β signaling via targeting HSP90β

Idiopathic pulmonary fibrosis is a progressive-fibrosing lung disease with high mortality and limited therapy, which characterized by myofibroblasts proliferation and extracellular matrix deposition. Myricetin, a natural flavonoid, has been shown to possess a variety of biological characteristics including anti-inflammatory and anti-tumor. In this study we explored the potential effect and mechanisms of myricetin on pulmonary fibrosis in vivo and vitro. The in vivo studies showed that myricetin effectively alleviated bleomycin (BLM)-induced pulmonary fibrosis. KEGG analysis of RNA-seq data indicated that myricetin could regulate the transforming growth factor (TGF)-β signaling pathway. In vitro studies indicated that myricetin could dose-dependently suppress TGF-β1/Smad signaling and attenuate TGF-β1-induced fibroblast activation and epithelial–mesenchymal transition (EMT). Molecular docking indicated that heat shock protein (HSP) 90β may be a potential target of myricetin, and MST assay demonstrated that the dissociation constant (Kd) of myricetin and HSP90β was 331.59 nM. We demonstrated that myricetin interfered with the binding of HSP90β and TGF-β receptor II and impeded fibroblast activation and EMT. In conclusion, myricetin impedes TGF-β1-induced lung fibroblast activation and EMT via targeting HSP90β and attenuates BLM-induced pulmonary fibrosis in mice.

Inhibition of herpes simplex virus by myricetin through targeting viral gD protein and cellular EGFR/PI3K/Akt pathway

Myricetin, a common dietary flavonoid, was reported to possess many different biological activities such as anti-oxidant, anti-inflammatory, and antiviral effects. In this study, we explored the anti-HSV effects and mechanisms of myricetin both in vitro and in vivo. The results showed that myricetin possessed anti-HSV-1 and HSV-2 activities with very low toxicity, superior to the effects of acyclovir. Myricetin may block HSV infection through direct interaction with virus gD protein to interfere with virus adsorption and membrane fusion, which was different from the nucleoside analogues such as acyclovir. Myricetin also down-regulate the cellular EGFR/PI3K/Akt signaling pathway to further inhibit HSV infection and its subsequent replication. Most importantly, intraperitoneal therapy of myricetin markedly improved mice survival and reduced virus titers in both lungs and spinal cord. Therefore, the natural dietary flavonoid myricetin has potential to be developed into a novel anti-HSV agent targeting both virus gD protein and cellular EGFR/PI3K/Akt pathway.

Potential of myricetin to restore the immune balance in dextran sulfate sodium-induced acute murine ulcerative colitis.

Myricetin is a bioactive compound in many edible plants with anti-inflammatory and anticarcinogenic activity. The current study aimed to determine the protective effects and mechanism of myricetin against ulcerative colitis (UC). Myricetin was orally administered at doses of 40 and 80mg/kg to C57BL/6 mice with UC induced using dextran sulfate sodium. The disease-associated index and colon length were determined at the end of the experiment, the proportion of Treg, Th1 and Th17 was analysed by cytometry, and cytokines were detected using ELISA. Myricetin (80mg/kg) ameliorated the severity of inflammation in acute UC and significantly improved the condition. Myricetin (80mg/kg) elevated the levels of IL-10 and transforming growth factor β. In addition, the proportion of regulatory T cells significantly increased in mice in the myricetin treatment group. Taking together, these results suggest that myricetin exhibits significant protective effects against UC and it could be used as a potential treatment for UC.

Myricetin improves endurance capacity by inducing muscle fiber type conversion via miR-499

BackgroundReprogramming of fast-to-slow myofiber switch can improve endurance capacity and alleviate fatigue. Accumulating evidence suggests that a muscle-specific microRNA, miR-499 plays a crucial role in myofiber type transition. In this study, we assessed the effects of natural flavonoid myricetin on exercise endurance and muscle fiber constitution, and further investigated the underlying mechanism of myricetin in vivo and in vitro.MethodsA total of 66 six-week-old male Sprague Dawley rats were divided into non-exercise or exercise groups with/without orally administered myricetin (50 or 150 mg/kg) for 2 or 4 weeks. Time-to-exhaustion, blood biochemical parameters, muscle fiber type proportion, the expression of muscle type decision related genes were measured. Mimic/ inhibitor of miR-499 were transfected into cultured L6 myotubes, the expressions of muscle type decision related genes and mitochondrial respiration capacity were investigated.ResultsMyricetin treatment significantly improved the time-to-exhaustion in trained rats. The enhancement of endurance capacity was associated with an increase of the proportion of slow-twitch myofiber in both soleus and gastrocnemius muscles. Importantly, myricetin treatment amplified the expression of miR-499 and suppressed the expression of Sox6, the down-stream target gene of miR-499, both in vivo and in vitro. Furthermore, inhibition of miR-499 overturned the effects of myricetin on down-regulating Sox6.ConclusionsMyricetin promoted the reprogramming of fast-to-slow muscle fiber type switch and reinforced the exercise endurance capacity. The precise mechanisms responsible for the effects of myricetin are not resolved but likely involve regulating miR-499/Sox6 axis.

The protective effects and mechanisms of myricetin on LPS-induced acute lung injury of BALB/c mice

Objective To investigate whether myricetin (Myr) exert protective effects on acute lung injury induced by LPS and to explore its underlying mechanisms. Methods A total of 72 mice were divided into the control group, model group, myricetin group and active group, 18 in each group. Male BALB/c mice of the myricetin were given an intragastric injection of Myr (50 mg/kg), and the active group dexamethasone (Dex, 5 mg/kg) 1 h before intranasal instillation of LPS. While the other groups were given the same volum saline. 24 hours after LPS exposure, mice were sacrificed and various samples were collected for further analysis. Both levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the bronchoalveolar lavage fluid (BALF) were measured by ELISA kits. The numbers of total cells, macrophages, and neutrophils in the BALF were also determined using differential leukocyte cell count method. The phosphorylations of nuclear factor-kappa B (NF-κB) and IκB were further detected by western blot analysis. Results Compared with the model group, the levels of macrophages and neutrophils in BALF in the myricetin and active groups significantly decreased (P<0.01), while the total protein and W/D ratio of the lung tissue significantly decreased (P<0.05). Compared with the model group, the levels of TNF-α (5.47 ± 2.54 pg/ml, 4.19 ± 0.50 pg/ml vs. 15.28 ± 1.27 pg/ml), IL-1β (336.20 ± 41.06 pg/ml, 247.99 ± 25.12 pg/ml vs. 464.88 ± 34.51pg/ml), the MPO (0.74 ± 0.12 U/g, 0.61 ± 0.08 U/g vs. 1.66 ± 0.07U/g) in the myricetin and active groups significantly decreased (P<0.01). Compared with the model group, the expression of p-IκB/IκB (0.61 ± 0.01, 0.59 ± 0.01 vs. 0.95 ± 0.01), p-NF-κB/NF-κB (0.54 ± 0.01, 0.59 ± 0.03 vs. 0.96 ± 0.02) of the lung tissue in the myricetin and active groups significantly decreased (P<0.01). Conclusions Collectively, these findings revealed that Myr may alleviate the LPS-induced acute lung injury via relief of inflammatory reactions associated with blockage of the NF-κB signaling pathway. Key words: Myricetin; Acute lung injury; Tumor necrosis factor-alpha; Interleukin-1beta; NF-kappa B; Inflammation; Bronchoalveolar lavage fluid; Mice

Myricetin Suppresses the Propagation of Hepatocellular Carcinoma Cells by Down-Regulating Expression of YAP

Background: Myricetin is a flavonoid that has protective effects against a variety of cancers. However, the mechanism of myricetin against hepatocellular carcinoma (HCC) is not fully understood. YAP have been shown to be essential for cancer initiation and progression. However, Whether YAP contributes to anti-cancer effects of myricetin remains unclear. This study aimed to investigate the effect of myricetin on HCC cells and identify the underlying mechanisms. Methods: The effects of myricetin on HCC cells were analyzed by cell counting, CCK-8, EdU labeling and flow cytometry assays. Western blot was used to determine the expression levels of LATS1/2, YAP and its potential target genes. In vitro kinase assay was used to determine kinase activity of LATS1/2. Xenograft tumor models were used to test whether myricetin sensitize HCC cancer to cisplatin in vivo. The mechanisms involved in myricetin effects on HCC cells growth, apoptosis and proliferation were analyzed by western blot and shRNA knock down assays. Findings: Here, we report that myricetin induces apoptosis and proliferation inhibition in HepG2 and Huh-7 cells. Myricetin inhibits expression of YAP by promoting its phosphorylation and subsequently degradation. Myricetin inhibits YAP expression by stimulating kinase activation of LATS1/2. Knockdown expression of LATS1/2 by shRNA attenuates myricetin-induced phosphorylation and degradation of YAP. Furthermore, myricetin sensitizes HCC cells to cisplatin treatment through inhibiting YAP and its target genes both in vitro and in vivo. Interpretation: The first identification of LATS1/2, YAP axis as a novel target of myricetin may help to design of novel strategies for human HCC prevention and therapy. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (grant Nos. 81600128 and 31501146), Natural Science Foundation of Shandong Province (grant Nos. BS2015SW024 and BS2015YY013), intramural Scientific Research Foundation from Binzhou Medical University (grant Nos. BY2014KYQD21 and BY2014KYQD22), Medical and Health Technology of Shandong, China (2016WS0007), and the Dominant Disciplines’ Talent Team Development Scheme of Higher Education of Shandong Province (2016052410). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: All animal studies were performed according to the guidelines and approval of the Ethical Committee of Binzhou Medical University.

Enhancing effects of myricetin on the osteogenic differentiation of human periodontal ligament stem cells via BMP-2/Smad and ERK/JNK/p38 mitogen-activated protein kinase signaling pathway

Myricetin is a flavonoid that found in berries, onions, and red grapes. It has been reported to have various pharmacological effects such as anti-inflammation, anti-oxidant and anti-cancer activities. However, the underlying mechanisms of myricetin on osteogenic differentiation remain unknown in human periodontal ligament stem cells (hPDLSCs). In this study, we investigated the ability of myricetin to increase osteogenic differentiation and its underlying molecular mechanisms. Myricetin significantly increased cell proliferation, alkaline phosphatase (ALP) activity, and alizarin red-mineralization activity in hPDLSCs in a dose-dependent manner. Furthermore, myricetin dose-dependently increased osteogenic-related mRNA and protein levels. Interestingly, it enhanced osteogenesis by up-regulating bone morphogenetic protein-2 (BMP-2), which induced the expression of BMP receptor type IB, Smad-1/5/9. It also enhanced the phosphorylation of extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinases (MAPKs) and Smads. We confirmed that the treatment of myricetin increased phosphorylated GSK-3β and β-catenin which is related to osteogenesis. In our studies, myricetin-induced increment of ALP activity was decreased by ERK (PD98059), JNK (SP600125), p38 (SB203580), and Smad 1/5/9 (LDN193189) inhibitors. ERK and p38 inhibitors showed the greatest inhibition among the four kinds of inhibitors.These results demonstrate that myricetin promoted osteogenic differentiation by the up-regulation of ALP activity and expression of osteogenic-related factors through BMP-2/Smad and ERK/JNK/p38 MAPK pathways.

Myricetin protects against lipopolysaccharide-induced disseminated intravascular coagulation by anti-inflammatory and anticoagulation effect

Objective: To explore the therapeutic effect and mechanism of myricetin on disseminated intravascular coagulation (DIC). Methods: The DIC model was established by injection of 60 mg/kg LPS in KM mice, and the treatment groups were injected myricetin with different concentrations (25 or 50 mg/kg) 30 min before the model was established. Both coagulation indicators and organ function were tested, including PT, APTT, fibrinogen, AST, ALT, BUN and tissue section. In vitro, the inflammatory model of RAW 264.7 macrophage cells were established by 10 μg/mL LPS. The treatment group was treated with 50 μmol/mL myricetin for 30 min before LPS, and the expression of TNF-α and p-NF-κB was detected, further to explore the therapeutic mechanism. Results: LPS-induced DIC led to a reduction of fibrinogen and a rise of PT, APTT, AST, ALT, BUN levels, but the treatment of myricetin significantly inhibited these abnormalities. Histopathology analysis also revealed that myricetin remarkably protected the liver and renal damage. In vitro, the expression of TNF-α and p-NF-κB induced by LPS was repressed by myricetin. Conclusions: This study provides new insights into the protective effects of myricetin in LPS-induced DIC by anticoagulant and anti-inflammatory via suppressing the activation of p-NF-κB which decreased TNF-α level.

Myricetin enhances on apoptosis induced by serum deprivation in PC12 cells mediated by mitochondrial signaling pathway

Polyphenols have many beneficial effects and an effective disease therapeutic auxiliary drug. Previously, myricetin, a polyphenol, had been reported to possess various biological effects on human physiology. However, mechanism of myricetin on apoptosis induced in PC12 cells is still unclear. PC12 cells were treated with myricetin in two concentration levels comprising 0.1 and 1 μM under serum-free condition. As a result, morphological changes were observed using trypan blue assay. DNA fragmentation was determined by DNA ladder assay to evaluate DNA damage levels. Western blotting results showed that cytosolic cytochrome c which was released from mitochondria. Subsequently, tumor suppressor gene p53, pro-apoptotic and anti-apoptotic Bcl-2 family proteins Bax and Bcl-2 were expressed. The caspase cascade reaction was induced through caspase 3 and 9 expression. From these results, it is suggested that myricetin significantly enhanced the apoptosis induced by serum deprivation in a dose-dependent manner in PC12 cells.

Myricetin Inhibits the Release of Glutamate in Rat Cerebrocortical Nerve Terminals

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 exerts anti-proliferative, anti-invasive, and pro-apoptotic effects on esophageal carcinoma EC9706 and KYSE30 cells via RSK2.

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.