PMID: 

Nutr Metab (Lond). 2019 ;16:25. Epub 2019 Apr 25. PMID: 31049071

Abstract Title: 

Myricetin ameliorates atherosclerosis in the low-density-lipoprotein receptor knockout mice by suppression of cholesterol accumulation in macrophage foam cells.

Abstract: 

Background: Myricetin, a major flavonoid found in several foods including berries, grapes and wine, exhibited strong antioxidant potency, yet the effect on atherosclerosis is not fully understood. In this study, we examined the effect of myricetin on lipid accumulation in macrophage and atherosclerosis in atherosclerosis-prone low density lipoprotein receptor-deficient () mice.Methods: mice were fed an atherogenic diet supplemented with myricetin (0.15% in the diet,/v) for 8 weeks. Body weight, adipose tissue weight, food intake, serum biochemical parameters were measured. Atherosclerosis lesions and macrophages accumulaton in lesions were analyzed and quantified. Macrophages were exposed to 20 μM of myricetin before incubated with oxidized low-density lipoprotein(ox-LDL) (25μg/mL) or Dil-ox-LDL for the indicated time. Lipid uptake and foam cell formation were evaluated by flow cytometry and microscopy. The intracellular lipids were extracted and measured. mRNA expression and protein of cholesterol metabolism related receptors were analyzed.Results: Myricetin administration reduced the weight, plasma lipid levels but not food intake inmice when fed an atherogenic diet. Myceritin-treatedmice displayed significantly less atherosclerotic areas and macrophages in the cross sections of the aortic root. There were also less lipophilic areas inOil red O staining of aorta from myceritin-treatedmice. Myceritin treatment also markedly ameliorated ox-LDL-induced cholesterol accumulation in macrophages. The expression of CD36 were decreased in myricetin treated macrophages with ox-LDL incubation, while scavenger receptors class A (SR-A) and scavenger receptors class B (SR-BI) expression was not altered, indicating that these effect of myricetin were dependent on CD36 pathway.Conclusions: Our findings indicated that myricetin suppressed cholesterol accumulation in macrophage foam cells by inhibition of CD36-mediated ox-LDL uptake, and suggested myricetin may have an important therapeutic function for atherosclerosis.

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PMID: 

Nutr Metab (Lond). 2019 ;16:27. Epub 2019 May 2. PMID: 31073320

Abstract Title: 

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

Abstract: 

Background: Reprogramming 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.Methods: A 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.Results: Myricetin 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.Conclusions: Myricetin 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.

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PMID: 

J Pharmacol Sci. 2019 May ;140(1):62-72. Epub 2019 May 4. PMID: 31130510

Abstract Title: 

Myricetin ameliorated ischemia/reperfusion-induced brain endothelial permeability by improvement of eNOS uncoupling and activation eNOS/NO.

Abstract: 

Disruption of the blood-brain barrier (BBB) has been considered as a major pathological change in stroke. eNOS/NO play a key role in maintain BBB function. Myricetin is one of the common flavones widely exists in food and fruit, show certain protective effect on the brain function. This experiment establishes oxygeneglucose deprivation and reoxygenation (OGD/R) brain cell model. The regulated effects of Myricetin on BBB function, eNOS/NO and eNOS uncoupling were evaluated. To investigate the molecular mechanism, Akt and Nrf2 inhibitor were also used. The result showed that Myricetin could significantly decreased the enhancement of endothelial permeability and inflammation in OGD/R model, in addition regulated eNOS/NO pathway. The regulate effect in endothelial permeability and eNOS activity by Myricetin were both decreased when combined with Akt inhibitor or Nrf2 inhibitor, and was abrogated when combined with Akt and Nrf2 inhibitor simultaneously. The regulated effect on eNOS uncoupling by Myricetin were abrogated when combined with Nrf2 inhibitor, but not with Akt inhibitor. In conclusion, Myricetin showed significant protect effect on ischemia/reperfusion-induced brain endothelial permeability, and related to simultaneously regulated Akt pathway and improvement of eNOS uncoupling through Nrf2 pathway.

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PMID: 

Mol Nutr Food Res. 2019 Jun 5:e1801393. Epub 2019 Jun 5. PMID: 31168926

Abstract Title: 

Myricetin Ameliorates Ethanol-Induced Lipid Accumulation in Liver Cells by Reducing Fatty Acid Biosynthesis.

Abstract: 

SCOPE: Alcoholic liver disease is a serious threat to human health. The development of drug candidates from complementary and alternative medicines is an attractive approach. Myricetin can be found in fruit, vegetables, and herbs. This study investigates the protective effect of myricetin on ethanol-induced injury in mouse liver cells.METHODS AND RESULTS: Oil-red O staining, assays of oxidative stress and measurements of inflammatory markers in mouse AML12 liver cells collectively demonstrate that myricetin elicits a curative effect on ethanol-induced injury. Next, the role of myricetin in the metabolic regulation of ethanol pathology in liver cells is assessed by gas chromatography coupled with mass spectrometry. Myricetin inhibits ethanol-stimulated fatty acid biosynthesis. Additionally, dodecanoic acid may be proposed as a potential biomarker related to ethanol pathology or myricetin therapy. It is also observed that myricetin enhances ethanol-induced inhibition of the mitochondrial electron transport chain. Moreover, fumaric acid is found to be a candidate biomarker related to ethanol toxicity or myricetin therapy. Quantitative reverse-transcription-PCR shows that ethanol-induced fatty acid synthase and sterol regulatory element-binding protein-1c mRNA levels are alleviated by myricetin. Finally, myricetin increases ethanol-induced inhibition of phosphorylation of AMP-activated protein kinase.CONCLUSION: These results elucidate the pharmacological mechanism of myricetin on ethanol-induced lipid accumulation.

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PMID: 

Nat Med. 2019 Jul 22. Epub 2019 Jul 22. PMID: 31332392

Abstract Title: 

Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome.

Abstract: 

Polycystic ovary syndrome (PCOS) is characterized by androgen excess, ovulatory dysfunction and polycystic ovaries, and is often accompanied by insulin resistance. The mechanism of ovulatory dysfunction and insulin resistance in PCOS remains elusive, thus limiting the development of therapeutics. Improved metabolic health is associated with a relatively high microbiota gene content and increased microbial diversity. This study aimed to investigate the impact of the gut microbiota and its metabolites on the regulation of PCOS-associated ovarian dysfunction and insulin resistance. Here, we report that Bacteroides vulgatus was markedly elevated in the gut microbiota of individuals with PCOS, accompanied by reduced glycodeoxycholic acid and tauroursodeoxycholic acid levels. Transplantation of fecal microbiota from women with PCOS or B. vulgatus-colonized recipient mice resulted in increased disruption of ovarian functions, insulin resistance, altered bile acid metabolism, reduced interleukin-22 secretion and infertility. Mechanistically, glycodeoxycholic acid induced intestinal group 3 innate lymphoid cell IL-22 secretion through GATA binding protein 3, and IL-22 in turn improved the PCOS phenotype. This finding is consistent with the reduced levels of IL-22 in individuals with PCOS. This study suggests that modifying the gut microbiota, altering bile acid metabolism and/or increasing IL-22 levels may be of value for the treatment of PCOS.

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PMID: 

Free Radic Res. 2019 Jul 10:1-311. Epub 2019 Jul 10. PMID: 31290351

Abstract Title: 

Modulation of selenium-dependent glutathione peroxidase activity enhances doxorubicin-induced apoptosis, tumor cell killing, and hydroxyl radical production in human NCI/ADR-RES cancer cells despite high-level P-glycoprotein expression.

Abstract: 

To define the role of glutathione peroxidase (GPx) in modulating the oxygen radical-related cytotoxicity of doxorubicin and HOin cells that overexpress P-glycoprotein (Pgp), the GPx activity of NCI/ADR-RES cancer cells was altered by growth in 0.5% serum with (MR-30 subline) or without (MR-0 subline) selenium supplementation. GPx activity increased from 2.2 nmol/min/mg (MR-0) to 22.5 nmol/min/mg (MR-30) when cells were grown in 30-nM selenium, 

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PMID: 

Front Pharmacol. 2019 ;10:647. Epub 2019 Jun 11. PMID: 31244660

Abstract Title: 

Myricetin Attenuated Diabetes-Associated Kidney Injuries and DysfunctionRegulating Nuclear Factor (Erythroid Derived 2)-Like 2 and Nuclear Factor-κB Signaling.

Abstract: 

Previous studies have suggested that myricetin (Myr) could promote the expression and nuclear translocation of nuclear factor (erythroid-derived 2)-like (Nrf2). This study aimed to investigate whether Myr could attenuate diabetes-associated kidney injuries and dysfunction in wild-type (WT) and Nrf2 knockdown (Nrf2-KD) mice.Lentivirus-mediated Nrf2-KD and WT mice were used to establish type 1 diabetes mellitus (DM) by streptozotocin (STZ) injection. WT and Nrf2-KD mice were then randomly allocated into four groups: control (CON), Myr, STZ, and STZ + Myr. Myr (100 mg/kg/day) or vehicle was administered for 6 months. Kidneys were harvested and weighed at the end of the experiment. Hematoxylin and eosin staining and Masson's trichrome staining were used to assess the morphology and fibrosis of the kidneys, respectively. Urinary albumin-to-creatinine ratio was used to test renal function. Western blotting was performed to determine oxidative-stress- or inflammation-associated signaling pathways. Real-time polymerase chain reaction (RT-PCR) was performed to detect the expression of fibrosis or inflammatory cytokines at the message Ribonucleic Acid (mRNA) level.In WT mice, Myr alleviated DM-induced renal dysfunction, fibrosis, and oxidative damage and enhanced the expression of Nrf2 and its downstream genes. After knockdown of Nrf2, Myr treatment partially but significantly mitigated DM-induced renal dysfunction and fibrosis, which might be associated with inhibition of the I-kappa-B (IκB)/nuclear factor-κB (NF-κB) (P65) signaling pathway.This study showed that Myr prevented DM-associated decreased expression of Nrf2 and inhibited IκB/NF-κB (P65) signaling pathway. Moreover, inhibition of IκB/NF-κB (P65) signaling pathway is independent of the regulation of Nrf2. Thus, Myr could be a potential treatment for preventing the development and progression of DM-associated kidney injuries and dysfunction.

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PMID: 

Anat Rec (Hoboken). 2019 Jul 2. Epub 2019 Jul 2. PMID: 31266091

Abstract Title: 

Myricetin Inhibits Breast Tumor Growth and Angiogenesis by Regulating VEGF/VEGFR2 and p38MAPK Signaling Pathways.

Abstract: 

Tumor angiogenesis is an important cause of tumor growth and metastasis. Myricetin is a flavonoid component used in traditional Chinese medicine that has been demonstrated to have anticancer activity. However, to the best of our knowledge, the effect of myricetin on tumor angiogenesis remains unknown. The present study reports the identification of myricetin as a potential chemopreventive agent by reason of its inhibition of tumor angiogenesis and demonstrates the anticancer effects of myricetin in vivo. Cell Counting Kit-8 assays revealed that myricetin inhibits the proliferation of tumor cells but not that of human umbilical vein endothelial cells (HUVECs), and a transwell assay demonstrated that myricetin could inhibit the migration of HUVECs. A rat aortic ring assay revealed that myricetin could also affect the development of microvessels and the formation of vascular networks. Further, an ELISA showed that myricetin reduced the levels of vascular endothelial growth factor (VEGF) in vivo and in vitro. Western blot analysis indicated that myricetin could downregulate VEGFR2 and p38MAPK. Therefore, myricetin could significantly inhibit tumor angiogenesis and has potential as a chemopreventive agent because of its inhibition to angiogenesis. Anat Rec, 2019.© 2019 Wiley Periodicals, Inc.

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PMID: 

Nat Med. 2019 Jul 22. Epub 2019 Jul 22. PMID: 31332389

Abstract Title: 

Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice.

Abstract: 

The gut microbiome is emerging as a key regulator of several metabolic, immune and neuroendocrine pathways. Gut microbiome deregulation has been implicated in major conditions such as obesity, type 2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease and cancer, but its precise role in aging remains to be elucidated. Here, we find that two different mouse models of progeria are characterized by intestinal dysbiosis with alterations that include an increase in the abundance of Proteobacteria and Cyanobacteria, and a decrease in the abundance of Verrucomicrobia. Consistent with these findings, we found that human progeria patients also display intestinal dysbiosis and that long-lived humans (that is, centenarians) exhibit a substantial increase in Verrucomicrobia and a reduction in Proteobacteria. Fecal microbiota transplantation from wild-type mice enhanced healthspan and lifespan in both progeroid mouse models, and transplantation with the verrucomicrobia Akkermansia muciniphila was sufficient to exert beneficial effects. Moreover, metabolomic analysis of ileal content points to the restoration of secondary bile acids as a possible mechanism for the beneficial effects of reestablishing a healthy microbiome. Our results demonstrate that correction of the accelerated aging-associated intestinal dysbiosis is beneficial, suggesting the existence of a link between aging and the gut microbiota that provides a rationale for microbiome-based interventions against age-related diseases.

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PMID: 

Nutrients. 2019 May 27 ;11(5). Epub 2019 May 27. PMID: 31137828

Abstract Title: 

Sulforaphane Prevents Hepatic Insulin Resistance by Blocking Serine Palmitoyltransferase 3-Mediated Ceramide Biosynthesis.

Abstract: 

Sulforaphane (SFA), a naturally active isothiocyanate compound from cruciferous vegetables used in clinical trials for cancer treatment, was found to possess potency to alleviate insulin resistance. But its underlying molecular mechanisms are still incompletely understood. In this study, we assessed whether SFA could improve insulin sensitivity and glucose homeostasis both in vitro and in vivo by regulating ceramide production. The effects of SFA on glucose metabolism and expression levels of key proteins in the hepatic insulin signaling pathway were evaluated in insulin-resistant human hepatic carcinoma HepG2 cells. The results showed that SFA dose-dependently increased glucose uptake and intracellular glycogen content by regulating the insulin receptor substrate 1 (IRS-1)/protein kinase B (Akt) signaling pathway in insulin-resistant HepG2 cells. SFA also reduced ceramide contents and downregulated transcription of ceramide-related genes. In addition, knockdown of serine palmitoyltransferase 3 (SPTLC3) in HepG2 cells prevented ceramide accumulation and alleviated insulin resistance. Moreover, SFA treatment improved glucose tolerance and insulin sensitivity, inhibited SPTLC3 expression and hepatic ceramide production and reduced hepatic triglyceride content in vivo. We conclude that SFA recovers glucose homeostasis and improves insulin sensitivity by blocking ceramide biosynthesis through modulating SPTLC3, indicating that SFA may be a potential candidate for prevention and amelioration of hepatic insulin resistance via a ceramide-dependent mechanism.

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