PMID: 

J Perinat Med. 2019 Jul 24. Epub 2019 Jul 24. PMID: 31339859

Abstract Title: 

Effect of bisphenol-A (BPA) on placental biomarkers for inflammation, neurodevelopment and oxidative stress.

Abstract: 

Background Bisphenol-A (BPA) is a widespread pollutant whose effects on pregnant women are poorly understood. Therefore, we investigated the effects of BPA on basal and bacteria-stimulated production of proinflammatory cytokines [interleukin (IL)-1β, tumor necrosis factor-α (TNF-α) and IL-6], anti-inflammatory mediators [soluble glycoprotein 130 (sgp) 130, heme oxidase-1 (HO-1) and IL-10] and biomarkers for neurodevelopment [brain-derived neurotrophic factor (BDNF)], and oxidative stress [8-isoprostane (8-IsoP)] by the placenta. Methods Placental explant cultures were treated with BPA (0-10,000 nM) in the presence or absence of 107 colony-forming unit (CFU)/mL heat-killed Escherichia coli for 24 h. Biomarker concentrations in conditioned medium were quantified by the enzyme-linked immunosorbent assay (ELISA). Results Under basal conditions, IL-1β and IL-6 production was enhanced by BPA in a dose-dependent manner. Sgp130, a soluble receptor that reduces IL-6 bioactivity, was suppressed by BPA at 1000-10,000 nM. BPA also enhanced BDNF production at 1000 and 10,000 nM, and 8-IsoP expression at 10 and 100 nM. For bacteria-treatedcultures, BPA increased IL-6 production at 100 nM and reduced sgp130 at 1000 nM but had no effect on IL-1β, TNF-α, BDNF, HO-1, 8-IsoP or IL-10 production. Conclusion BPA may increase placental inflammation by promoting IL-1β and IL-6 but inhibiting sgp130. It may also disrupt oxidative balance and neurodevelopment by increasing 8-IsoP and BDNF production.

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PMID: 

Life Sci. 2019 Jun 15:116578. Epub 2019 Jun 15. PMID: 31211996

Abstract Title: 

Selenium protection against mercury neurotoxicity: Modulation of apoptosis and autophagy in the anterior pituitary.

Abstract: 

AIMS: The aim of the present study is to shed light on the modulating action of selenium on two of the most crucial cellular pathways; apoptosis and autophagy and the possible interplay between them in determining the pituitary fate in the context of mercury intoxication through demonstration of the molecular, histopathological, immunohistochemical, and ultrastructural features of selenium mercury-treated adenohypophysis.METHODS: Thirty adult Sprague Dawley male albino rats were assigned into control group, mercury-treated group and mercury‑selenium concomitantly-treated group. The adenohypophysis was subjected to structural, molecular and protein expression assessment of autophagy and apoptotic markers and western blotted analysis of Beclin 1 as a key cross-regulator of autophagy and apoptosis.KEY FINDINGS: Selenium treatment ameliorated the mercury-induced apoptosis detected by improvement in PCR and immunohistochemical expression of the apoptotic markers Bax, Bcl-2 and Caspase-3. Selenium also improved mercury-induced autophagic dysfunction with statistically significant improvement in western blotted levels of the autophagy markers LC3I, LC3II and Beclin1. The histopathological and ultrastructural studies strongly confirmed those findings.SIGNIFICANCE: The crosstalk between the apoptotic Bcl-2 family of proteins and the autophagic Beclin-1LC3 pathway in the context of mercury intoxication paves the way for developing novel effective treatment strategies for several mercury-induced pituitary diseases.

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PMID: 

Biol Trace Elem Res. 2019 Jun 22. Epub 2019 Jun 22. PMID: 31230209

Abstract Title: 

Selenium-Rich-Yeast Protects Against Aluminum-Induced Activating Nuclear Xenobiotic Receptors and Triggering Inflammation and Cytochromes P450 Systems in Mice Heart.

Abstract: 

Aluminum (Al) poisoning is linked to the development of cardiovascular diseases, and dietary supplementation with selenium-rich-yeast (SeY) has been shown to prevent inflammatory conditions. We evaluated the preventive effect of SeY on Al-induced cardiotoxicity, and the possible underlying mechanisms. Mice were treated with SeY (0.1 mg/kg) and/or Al (10 mg/kg) by oral gavage for 4 weeks. Histopathological damage was observed in the heart of Al-treated mice, in addition to the transcriptional up/downregulation of nuclear xenobiotic receptors (NXRs), inflammatory cytokines and 15 CYP450s genes. SeY significantly inhibited these Al-induced histopathological and molecular changes, and restored these indicators to the control levels. These results suggest that SeY exerts a cardio-protective effect against Al-induced toxicity through the NXR system, inflammatory cytokines, and CYP450s genes.

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PMID: 

Artif Cells Nanomed Biotechnol. 2018 ;46(sup3):S180-S191. Epub 2019 Jan 28. PMID: 30691320

Abstract Title: 

Myricetin nanoliposomes induced SIRT3-mediated glycolytic metabolism leading to glioblastoma cell death.

Abstract: 

As the most aggressive and malignant glioma, glioblastoma multiforme (GBM) abnormally expresses genes that mediate glycolytic metabolism and tumour cell growth. In this study, we investigated myricetin incorporated nanoliposomes and ascertained their prospect in effectively treating cancer via the employment of the GBM cell line DBTRG-05MG. Notably, the myricetin nanoliposomes (MYR-NLs) displayed potent inhibition of proliferation and significantly regulated the levels of proteins related to both glycolytic metabolism and cell survival. Most importantly, SIRT3 and phosphorylated p53 were also down-regulated by MYR-NLs, indicating that the MYR-NLs inhibited GBM cell growth through the SIRT3/p53-mediated PI3K/Akt-ERK and mitochondrial pathways. Our findings thus provide rational evidence that liposomal myricetin targeted at alternative cell death pathways may be a useful adjuvant therapy in glioblastoma treatment.

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PMID: 

Food Funct. 2019 Mar 20 ;10(3):1465-1477. PMID: 30776032

Abstract Title: 

Myricetin alleviated hepatic steatosis by acting on microRNA-146b/thyroid hormone receptor b pathway in high-fat diet fed C57BL/6J mice.

Abstract: 

Hepatic microRNAs (miRs) regulate local thyroid hormone (TH) action and TH-related lipid metabolism. We previously found that myricetin effectively ameliorated hepatic steatosis by targeting PPAR signaling pathway, in which the differentially expressed genes were TH-responsive. The present study was designed to explore the mechanism by which myricetin regulated miR-dependent TH action and lipid metabolism on high-fat diet (HFD)-induced hepatic steatosis. C57BL/6J mice were fed a HFD with or without 100 mg kg-1 myricetin by oral gavage for 16 weeks (n = 8 for each group). The results showed that myricetin improved HFD-induced hepatic steatosis, increased serum TH levels and hepatic type 1 deiodinase (DIO1) activities, and elevated energy expenditure in relation to the HFD mice. Meanwhile, myricetin inhibited miR-205 and miR-146b up-regulation induced by HFD, and also up-regulated their targets, Dio1 and thyroid hormone receptor b (TRb) expression, at both the transcriptional and translational levels, accompanied by the regulation of TH responsive lipid metabolism genes. Overexpression or knockdown of miR-205 failed to affect Dio1 mRNA and protein levels in primary mouse hepatocytes. Myricetin directly decreased miR-146b expression in miR-146b mimic-treated hepatocytes to elevate TRb levels. However, the beneficial effects of myricetin on hepatic TH action and lipid metabolism were abolished by TRb siRNA in free fatty acid (FFA)-treated hepatocytes. Our results indicated that myricetin attenuated hepatic steatosis via the miR-146b/TRb pathway and should be considered for the management of NAFLD conditions.

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PMID: 

J Cancer Res Ther. 2019 Jan-Mar;15(1):157-163. PMID: 30880773

Abstract Title: 

Myricetin ameliorates cytokine-induced migration and invasion of cholangiocarcinoma cells via suppression of STAT3 pathway.

Abstract: 

Aim of Study: Cholangiocarcinoma (CCA) is an aggressive cancer with considerable metastatic potential. Various cytokines secreted by tumor cells or cells in the tumor environment can promote the metastasis of CCA. The aim of the present study was to investigate the effect of myricetin on the inhibition of cytokine-induced migration and invasion and the associated cellular mechanisms in human CCA cells.Materials and Methods: CCA KKU-100 cells were treated with a pro-inflammatory cytokine mixture consisting of interleukin-6, interferon-γ, and tumor necrosis factor-α. The migratory and invasive ability of KKU-100 cells were determined using a wound-healing assay and transwell invasion assay. The effect of myricetin on cytokine-induced STAT3 activation in CCA cells was determined using Western blot analysis. The real-time polymerase chain reaction was performed to determine messenger RNA expression.Results: Myricetin significantly inhibited cytokine-induced migration and invasion of KKU-100 cells. Detailed molecular analyses revealed that myricetin suppressed the activation of the STAT3 pathway, evidently by a decrease of the active phospho-STAT3 protein expression after myricetin treatment. The cytokine-mediated upregulation of metastasis- and inflammatory-associated genes, which are downstream genes of STAT3 including the intercellular adhesion molecule-1, matrix metalloproteinase-9, inducible nitric oxide synthase, and cyclo-oxygenase 2 (COX-2), were also significantly abolished by myricetin treatment. Moreover, the anti-migratory and anti-invasive activities of a widely prescribed COX inhibitor, indomethacin, were also revealed.Conclusion: This finding reveals the anti-metastatic effect of myricetin against CCA cells which is mediated partly through suppression of the STAT3 pathway. This compound could be potentially useful as a therapeutic agent against CCA.

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PMID: 

Exp Ther Med. 2019 Apr ;17(4):3083-3091. Epub 2019 Feb 15. PMID: 30906480

Abstract Title: 

Myricetin attenuates the severity of seizures and neuroapoptosis in pentylenetetrazole kindled mice by regulating the of BDNF-TrkB signaling pathway and modulating matrix metalloproteinase-9 and GABA.

Abstract: 

Currently available antiepileptic drugs are effective; however, frequently associated with adverse effects that limit their therapeutic value. Compounds that target the molecular events underlying epilepsy, with minor or no adverse effects, would be of clinical value. Matrix metalloproteinase-9 (MMP-9) and the brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling pathway may be involved in epileptogenesis. The current study investigated the effects of the plant-derived hydroxyflavone, myricetin, in a pentylenetetrazole (PTZ)-induced mouse model of epilepsy. Mice received an intraperitoneal injection of 35 mg/kg body weight PTZ on alternate days (13 injections) and were observed for 30 min following each PTZ injection. Myricetin (100 or 200 mg/kg body weight) was administered orally to the treatment groups (n=18/group) for 26 days, 30 min prior to each PTZ injection. Treatment with myricetin reduced seizure and mortality rates. Increased apoptotic cell count and elevated expression levels of apoptotic proteins caused by PTZ kindling were downregulated following treatment with myricetin. The BDNF-TrkB signaling pathway and MMP-9 expression levels were regulated by myricetin. Expression ofγ-aminobutyric acid A (GABA) receptor and glutamic acid decarboxylase 65, as well as the glutamate/GABA balance, were restored following treatment with myricetin. The results of the present study indicated that myricetin may exert protective effects by regulating the molecular events associated with epileptogenesis.

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PMID: 

Biomed Res Int. 2019 ;2019:3746326. Epub 2019 Mar 7. PMID: 30956980

Abstract Title: 

Microarray Based Functional Analysis of Myricetin and Proteomic Study on Its Anti-Inflammatory Property.

Abstract: 

Myricetin has been reported as a promising chemopreventive compound with multiple biofunctions. To evaluate its influence on gene expressions in genome-wide set and further investigate its anti-inflammatory property, the present study performed Gene Ontology and Ingenuity Pathway Analysis (IPA) to describe the basic gene expression characteristics by myricetin treatment in HepG2 cells, confirmed its multi-biofunction by real-time fluorescent quantitative PCR (RT-qPCR), and further verified its anti-inflammatory property by Western blotting and bio-plex-based cytokines assay. The IPA data showed that 337 gene expressions (48% of the top molecules) are disturbed over 2-fold, and the most possible biofunctions of myricetin are the effect on"cardiovascular disease, metabolic disease, and lipid metabolism,"via regulation of 28 molecules with statistic score of 46. RT-qPCR data confirmed the accuracy of microarray data, and cytokines assay results indicated that 6 of the total 27 inflammatory cytokine secretions were significantly inhibited by myricetin pretreatment, including TNF-, IFN-, IL-1, IL-1, IL-2, and IL-6. The present study is the first time to elucidate the multi-function of myricetin in genome-wide set by IPA analysis and verify its anti-inflammatory property by proteomics of cytokines assay. Therefore, these results enrich the comprehensive bioactivities of myricetin and reveal that myricetin has powerful anti-inflammatory property, which provides encouragement forstudies to verify its possible health benefits.

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PMID: 

Cells. 2019 04 17 ;8(4). Epub 2019 Apr 17. PMID: 30999669

Abstract Title: 

Myricetin Suppresses the Propagation of Hepatocellular Carcinoma via Down-Regulating Expression of YAP.

Abstract: 

Myricetin is a naturally occurring flavonoid with protective effects against a variety of cancers. However, the molecular mechanism of myricetin against hepatocellular carcinoma (HCC) has still not been fully elucidated. Previous studies have indicated that YAP is essential for cancer initiation and progression. However, whether YAP contributes to the anti-cancer effects of myricetin remains unclear. Herein, we aimed to investigate the effect of myricetin on HCC, and identify the underlying mechanisms. We report that myricetin induced apoptosis and proliferation inhibition in HepG2 and Huh-7 cells. Myricetin inhibited expression of YAP by promoting its phosphorylation and subsequent degradation. Myricetin inhibited YAP expression by stimulating kinase activation of LATS1/2. Knockdown expression of LATS1/2 by shRNA attenuated myricetin-induced phosphorylation and degradation of YAP. Furthermore, myricetin sensitized HCC cells to cisplatin treatment through inhibiting YAP and its target genes, both in vitro and in vivo. The identification of the LATS1/2-YAP pathway as a target of myricetin may help with the design of novel strategies for human HCC prevention and therapy.

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PMID: 

Eur J Med Res. 2019 Apr 26 ;24(1):20. Epub 2019 Apr 26. PMID: 31027517

Abstract Title: 

Protective functions of myricetin in LPS-induced cardiomyocytes H9c2 cells injury by regulation of MALAT1.

Abstract: 

BACKGROUND: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a crucial mediator in response to inflammation. Myricetin protects cardiomyocytes against inflammatory injury. However, it's still unexplored whether myricetin exerted anti-inflammatory properties via MALAT1. The purpose of our study was to validate the cardio-protective function of myricetin against myocarditis and its underlying mechanism in vitro.METHODS: H9c2 cells were pre-incubated with myricetin before stimulation with lipopolysaccharide (LPS). Enforced silence of MALAT1 was achieved by transducing short hairpin (sh)-MALAT1 into H9c2 cells. Next, cell viability and apoptotic cells were detected with cell counting kit-8 (CCK-8) and Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) apoptosis detection kit, respectively. Western blot assay was conducted to examine apoptosis-relative proteins, pro-inflammatory factors, and signaling regulators. Quantitative real-time PCR (qRT-PCR) was performed to quantify pro-inflammatory factors and MALAT1 at mRNA levels. Enzyme-linked immune sorbent assay (ELISA) was employed to determine protein concentration of pro-inflammatory factors.RESULTS: Myricetin ameliorated LPS-elicited reduction of cell viability, augment of apoptosis, and overexpression of monocyte chemo-attractant protein-1 (MCP-1) and interleukin-6 (IL-6) in H9c2 cells. Meanwhile, phosphorylation of p65 and inhibitor of nuclear factor kappa B alpha (IκBα) were suppressed. Besides, myricetin enhanced the expression of MALAT1 which was originally down-regulated by LPS. However, the protective effects of myricetin against LPS-caused inflammatory lesions were abrogated in MALAT1-deficiency cells, with the restored phosphorylation of p65 and IκBα.CONCLUSION: Myricetin possessed an anti-inflammatory function against LPS-induced lesions in cardiomyocytes. Mechanically, myricetin up-regulated MALAT1, blocked LPS-evoked activation of nuclear factor-κB (NF-κB) inflammatory pathway, and, finally, exerted cardio-protective effects.

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