PMID: 

J Photochem Photobiol B. 2019 May ;194:84-95. Epub 2019 Mar 21. PMID: 30933875

Abstract Title: 

Apigenin restores impairment of autophagy and downregulation of unfolded protein response regulatory proteins in keratinocytes exposed to ultraviolet B radiation.

Abstract: 

Ultraviolet (UV)-B radiation is a major environmental risk factor that is responsible for the development and progression of many skin cancers. Apigenin, a type of bioflavonoid, has been reported to inhibit UVB-induced skin cancer. However, how apigenin functions in keratinocytes with UV damage remains unclear. In this study, by lactate dehydrogenase (LDH) release assay, we found that apigenin treatment increased cell death in the primary human epidermal keratinocytes (HEKs) and the cutaneous squamous cell carcinoma cell line COLO-16. Apigenin treatment reduced microtubule-associated protein 1 light chain 3 (LC3)-II turnover, acridine orange staining and GFP-LC3 puncta in both cell types, suggesting autophagy inhibition. However, apigenin treatment restored the inhibition of autophagy in UVB-challenged HEKs. Moreover, apigenin treatment restored the UVB-induced downregulation of ataxia-telangiectasia mutated (ATM), ataxia-telangiectasia, Rad3-related (ATR) and the unfolded protein response (UPR) regulatory proteins, BiP, IRE1α and PERK in HEKs. Apigenin treatment also inhibited UVB-induced apoptosis and cell death in HEKs. In addition, autophagy inhibition by autophagy-related gene (ATG) 5 RNA interference interrupted apigenin-induced restoration of ATR, ATM and BiP, which were downregulated in HEKs exposed to UVB radiation. Our findings indicate that apigenin exhibits a novel protective effect in keratinocytes with UVB damage, suggesting potential application as a photoprotective agent.

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PMID: 

Phytother Res. 2019 Aug 30. Epub 2019 Aug 30. PMID: 31468624

Abstract Title: 

Apigenin from Croton betulaster Müll restores the immune profile of microglia against glioma cells.

Abstract: 

The flavonoid apigenin, extracted from the Brazilian plant Croton betulaster Müll. has demonstrated the ability to inhibit proliferation, induce differentiation, and modify the inflammatory profile of glioma cells. The aim of the present study was to evaluate the effect of apigenin on chemotaxis and regulation of inflammatory cytokines of microglia cells and these impacts onglioma cell growth. In cultures of isolated rat microglia, it was observed that apigenin induced changes in Iba1-positive cells to an ameboid phenotype, associated to an increase in the expression of the activated M1 profile marker OX-42 and iNOS and a reduction in the expression of the M2 profilemarker CD206. Besides, apigenin modulated the tumor necrosis factor and IL-10 release by microglia. Treatment of C6 glioma cells with conditioned medium of microglia treated with apigenin-induced reduction of tumor migration and viability, associated with significant reduction in IL-6 levels. On theother hand, treatment of C6 cells with apigenin-induced microglia chemotaxis to glioma in vitro. Moreover, apigenin treatment of microglia/C6 co-cultures induced preferentially reduction in the viability of C6 cells and increased microglia-activated phenotype, associated with a change in the balance of TNF/IL-10 levels. Together, these results demonstrated that the flavonoid apigenin restores the immune profile of microglia against glioma cells.

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PMID: 

Cancer Genomics Proteomics. 2019 Nov-Dec;16(6):421-431. PMID: 31659097

Abstract Title: 

Whole Transcriptomic Analysis of Apigenin on TNFα Immuno-activated MDA-MB-231 Breast Cancer Cells.

Abstract: 

BACKGROUND: Triple-negative breast cancer is categorized by a lack of hormone receptors, inefficacy of anti-estrogen or aromatase inhibitor chemotherapies and greater mortality rates in African American populations. Advanced-stage breast tumors have a high concentration of tumor necrosis factor-α (TNFα) throughout the tumor/stroma milieu, prompting sustained release of diverse chemokines (i.e. C-C motif chemokine ligand 2 (CCL2)/CCL5). These potent chemokines can subsequently direct mass infiltration of leukocyte sub-populations to lodge within the tumor, triggering a loss of tumor immune surveillance and subsequent rapid tumor growth. Previously, we demonstrated that in the MDA-MB-231 TNBC cell line, TNFα evoked a rise in immune signaling proteins: CCL2, granulocyte macrophage colony-stimulating factor, interleukin (IL)1α, IL6 and inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKε) all of which were attenuated by apigenin, a dietary flavonoid found in chamomile and parsley.MATERIALS AND METHODS: The present work elucidates changes evoked by TNFα in the presence or absence of apigenin by examining the entire transcriptome for mRNA and long intergenic non-coding RNA with Affymetrix Hugene-2.1_ST human microarrays. Differential gene-expression analysis was conducted on 48,226 genes.RESULTS: TNFα caused up-regulation of 75 genes and down-regulation of 10. Of these, apigenin effectively down-regulated 35 of the 75 genes which were up-regulated by TNFα. These findings confirm our previous work, specifically for the TNFα-evoked spike in IL1A vs. untreated controls [+21-fold change (FC), p

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PMID: 

Am J Transl Res. 2019 ;11(8):4683-4695. Epub 2019 Aug 15. PMID: 31497191

Abstract Title: 

Quercetin improves blood-brain barrier dysfunction in rats with cerebral ischemia reperfusion via Wnt signaling pathway.

Abstract: 

Reperfusion therapy after cerebral ischemia often leads to reperfusion injury which may cause brain edema and blood-brain barrier (BBB) dysfunction. As a natural bioflavonoid, quercetin may exert protective effects on BBB dysfunction. This study aimed to investigate effects of quercetin in a rat model of global cerebral ischemia reperfusion (I/R) injury and explore the potential mechanism. Male rats were randomly divided into 4 groups: sham group, I/R group, quercetin-treated group (25μmol/kg twice daily for 3 consecutive days before I/R), and quercetin/DKK-1-treated group. Global cerebral I/R was induced by bilateral common carotid artery occlusion combined with hypotension for 20 min and reperfusion for 24 h. Neurological function was scored, and then rats were sacrificed. Thebrain was harvested for HE staining, NeuN staining, and detection of brain water content. The BBB structure and permeability were examined by transmission electron microscopy and Evans blue extravasation, respectively. The protein expression of MMP-9, ZO-1, Claudin-5, β-catenin, and GSK-3β, and the mRNA expression of Axin and LEF1 were detected in either the absence or presence of Wnt/β-catenin inhibitor DKK-1. Results showed that quercetin reduced brain edema and BBB leakage, and improved BBB dysfunction. Quercetin could increase the expression of ZO-1, Claudin-5, β-catenin, and LEF1, and decrease the expression of MMP-9, GSK-3β and Axin. And all these protective effects of quercetin could be reversed by DKK-1. Thus, quercetin can alleviate BBB dysfunction after global cerebral I/R in rats and the mechanism may be related to the activation of canonical Wnt/β-catenin signaling pathway.

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PMID: 

Phytother Res. 2019 Sep 9. Epub 2019 Sep 9. PMID: 31497913

Abstract Title: 

Quercetin protects against cisplatin-induced acute kidney injury by inhibiting Mincle/Syk/NF-κB signaling maintained macrophage inflammation.

Abstract: 

Acute kidney injury (AKI) with high incidence and mortality is the main cause of chronic kidney disease. Previous studies have indicated that quercetin, an abundant flavonoid in plants, exhibited renoprotective role in AKI. However, the underlying mechanism is largely unknown. In this study, we try to explore whether quercetin protects against AKI by inhibiting macrophage inflammation via regulation of Mincle/Syk/NF-κB signaling. The results demonstrated that quercetin can significantly inhibit expression and secretion of IL-1β, IL-6, and TNF-α in LPS-induced bone marrow-derived macrophages (BMDMs) and reduce activity of Mincle/Syk/NF-κB signaling in vitro. We also found that quercetin can strongly reduce the concentration of serum creatinine, BUN, IL-1β, IL-6, and TNF-α in cisplatin-induced AKI model. Furthermore, quercetin down-regulated protein levels of Mincle, phosphorylated Syk and NF-κB in kidney macrophages of AKI, as well as inhibited M1, up-regulated M2 macrophage activity. Notably, the down-regulation of LPS-induced inflammation by quercetin was reversed after adding TDB (an agonist of Mincle) in BMDMs, suggesting that quercetin suppresses macrophage inflammation may mainly through inhibiting Mincle and its downstream signaling. In summary, these findings clarified a new mechanismof quercetin improving AKI-induced kidney inflammation and injury, which provides a new drug option for the clinical treatment of AKI.

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PMID: 

J Appl Microbiol. 2019 Sep 11. Epub 2019 Sep 11. PMID: 31509634

Abstract Title: 

Quercetin reduces atherosclerotic lesions by altering the gut microbiota and reducing atherogenic lipid metabolites.

Abstract: 

AIMS: Epidemiological studies have correlated cardiovascular disease and atherosclerosis with lifestyle factors such as sedentary behaviour and a high-calorie diet. Recent studies of pathogenesis have highlighted the significance of the intestinal microbiota and chronic inflammation with respect to both the onset and development of atherosclerosis. This study examined the hypothesis that the oral administration of quercetin to low-density lipoprotein receptor-null (Ldlr) mice would improve gut health by altering the gut microbiota and controlling the levels of atherogenic lipid metabolites and proinflammatory mediators in the intestine and serum.METHODS AND RESULTS: Mice were maintained on a high-fat diet with or without oral quercetin administration for 12 weeks. Quercetin treatment suppressed body weight gains and reduced the extent of atherosclerotic lesions in the aortic sinus. Reduced malondialdehyde and increased interleukin 6 levels further indicated the protective effect of quercetin against immune/inflammatory responses and oxidative stress.Furthermore, quercetin led to decreased intestinal levels of cholesterol, lysophosphatidic acids and atherogenic lysophosphatidylcholine (LPC 18:1) and an increased level of coprostanol. A phylum-level microbial analysis revealed that quercetin treatment reduced the abundance of Verrocomicrobia andincreased microbiome diversity and the abundances of Actinobacteria, Cyanobacteria and Firmicutes. A Spearman analysis revealed negative correlations of Actinobacteria with intestinal and plasma LPC 18:1 and caecal cholesterol levels and of Firmicutes and Cyanobacteria with the plasma LPC 18:1 level.CONCLUSIONS: This study demonstrated the ability of quercetin treatment to reduce lipid levels, as well as the areas of atherosclerotic lesions and sizes of plaques. This treatment also altered the composition of the gut microbiota and decreased the levels of atherogenic lipid metabolites.SIGNIFICANCE AND IMPACT OF THE STUDY: Oral quercetin treatment may represent a new approach to mitigating the onset and development of atherosclerosis.

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PMID: 

Int J Mol Med. 2019 Sep ;44(3):893-902. Epub 2019 Jul 3. PMID: 31524223

Abstract Title: 

Quercetin protects against atherosclerosis by regulating the expression of PCSK9, CD36, PPARγ, LXRα and ABCA1.

Abstract: 

The aim of this study was to investigate the mechanisms through which quercetin protects against atherosclerosis (AS) in apoE‑/‑ mice by regulating the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), cluster of differentiation 36 (CD36), peroxisome proliferator‑activated receptor γ (PPARγ), liver X receptor α (LXRα) and ATP binding cassette transporter A1 (ABCA1). We established an animal model of high‑fat diet induced AS using apoE‑/‑ mice. H&E, Oil Red O and Masson's trichrome staining were performed on aortic sinus and liver tissue sections to evaluate the histopathology, lipid accumulation and collagen deposition, respectively. Filipin staining was performed to detect free cholesterol (FC) in the aortic sinus. ELISA was performed to measure the serum levels of lipids including total cholesterol (TC), triglyceride (TG), high‑density lipoprotein‑cholesterol (HDL‑C), low‑density lipoprotein‑cholesterol (LDL‑C) and oxidized low‑density lipoprotein (oxLDL), as well as the levels of inflammatory cytokines, including tumor necrosis factor (TNF)‑α, interleukin (IL)‑6 and IL‑10. Western blot analysis was performed to analyze the protein expression levels of PCSK9, CD36, PPARγ, LXRα and ABCA1 in both the aorta and liver tissue. H&E staining revealed the presence of atherosclerotic plaques in the aortic sinus. Oil Red O staining revealed the existence of massive red‑stained lipids in the aortic sinus and Masson's trichrome staining revealed decreased collagen fibers and increased plaque instability. Filipin staining revealed that free cholesterol levels in the aorta sinus were increased. In addition, H&E staining suggested hepatocyte structural disorder in the model group, and Oil Red O staining revealed a cytoplasm filled with lipid droplets, which contained a large amount of red‑stained lipids. Masson's trichrome staining revealed that the liver tissue of the model group had fewer collagen fibers compared with that of the control group. Moreover, the mice in the model group had higher serum TC, LDL‑C, oxLDL, TNF‑α and IL‑6 levels, and lower IL‑10 levels. The protein expression levels of PCSK9 and CD36 were increased, while those of PPARγ, LXRα and ABCA1 were decreased in the aortas and livers of the model group mice. However, treatment with quercetin attenuated all these effects. On the whole, these results demonstrate that quercetin prevents the development of AS in apoE‑/‑ mice by regulating the expression of PCSK9, CD36, PPARγ, LXRα and ABCA1.

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PMID: 

J Cancer. 2019 ;10(19):4509-4521. Epub 2019 Jul 25. PMID: 31528215

Abstract Title: 

Combination of quercetin and cisplatin enhances apoptosis in OSCC cells by downregulating xIAP through the NF-κB pathway.

Abstract: 

While cisplatin is a first-line chemotherapeutic drug commonly used to treat patients with oral squamous cell carcinoma (OSCC), the cisplatin-resistance poses a major challenge for its clinical application. Recent studies have shown that quercetin, a natural flavonoid found in various plants and foods possesses an anti-cancer effect. The following study examined the combined effect of quercetin and cisplatin on OSCC apoptosisand(using a mice tumor model). We found that quercetin promotes cisplatin-induced apoptosis in human OSCC (cell lines Tca-8113 and SCC-15) by down-regulating NF-κB. Pretreatment of cancer cells with quercetin inhibited the phosphorylation Akt and IKKβ, and led to the suppression of NF-κB and anti-apoptotic protein xIAP. In addition, we observed that the pretreatment of cancer cells with quercetin improves extrinsic and intrinsic apoptosis by activating caspase-8 and caspase-9, respectively. Ourdata also indicated that the combination of quercetin and cisplatin may inhibit the xenograft growth in mice. To sum up, our results provide a new evidence for the application of quercetin and cisplatin in OSCC therapy.

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PMID: 

J Food Sci. 2019 Oct ;84(10):3045-3053. Epub 2019 Sep 17. PMID: 31529802

Abstract Title: 

Quercetin Mitigates Hepatic Insulin Resistance in Rats with Bile Duct Ligation Through Modulation of the STAT3/SOCS3/IRS1 Signaling Pathway.

Abstract: 

Insulin resistance (IR) and inflammatory mediators are correlated with hepatic fibrosis. Quercetin is a bioflavonoid with well-known antidiabetic and antifibrotic properties. Bile duct ligation (BDL) is a surgical model performed on animals to produce a murine model in which increased oxidative stress occurs, which results in liver fibrosis. Our study aimed to determine whether quercetin improves hepatic IR as well as hepatic fibrosis in rats experiencing BDL. Male Wistar rats were allocated to four groups according to a random pattern, including a sham group, a sham and quercetin group (30 mg/kg/day), a BDL alone group, and a BDL and quercetin group (30 mg/kg/day). Evaluation of STAT3, SOCS3, IRS1, Rac1, Rac1-GTP, Sp1, NOX1, HIF-1α, and ERK1 expression was performed by RT-PCR along with the western blot analytical technique in liver tissue. The antidiabetic impact of quercetin wasassociated with reduction in mRNA and expression of protein in STAT3 and SOCS3, along with an increase in IRS1. The antifibrotic effect of quercetin was also determined by downregulation of mRNA or the levels of protein expression of Rac1-GTP, Rac1, HIF-1α, NOX1, and Sp1, along with ERK1. Our study indicates that quercetin may improve hepatic fibrosis via inhibiting ROS-associated inflammation as well as ameliorating hepatic IR by beneficial regulation of the STAT3/SOCS3/IRS1 signaling pathway.

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PMID: 

Biomed Res Int. 2019 ;2019:6282635. Epub 2019 Aug 20. PMID: 31531360

Abstract Title: 

Quercetin Inhibits Inflammatory Response Induced by LPSin Human Gingival Fibroblasts via Suppressing NF-B Signaling Pathway.

Abstract: 

Quercetin, a natural flavonol existing in many food resources, has been reported to be an effective antimicrobial and anti-inflammatory agent for restricting the inflammation in periodontitis. In this study, we aimed to investigate the anti-inflammatory effects of quercetin on() lipopolysaccharide- (LPS-) stimulated human gingival fibroblasts (HGFs). HGFs were pretreated with quercetin prior to LPS stimulation. Cell viability was evaluated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. The levels of inflammatory cytokines, including interleukin-1(IL-1), interleukin-6 (IL-6), and tumor necrosis factor-(TNF-), along with chemokine interleukin-8 (IL-8), were determined by enzyme-linked immunosorbent assay (ELISA). The mRNA levels of IL-1, IL-6, IL-8, TNF-, IB, p65 subunit of nuclear factor-kappa B (NF-B), peroxisome proliferator-activated receptor-(PPAR-), liver X receptor(LXR), and Toll-like receptor 4 (TLR4) were measured by real-time quantitative PCR (RT-qPCR). The protein levels of IB, p-IB, p65, p-p65, PPAR-, LXR, and TLR4 were characterized by Western blotting. Our results demonstrated that quercetin inhibited the LPS-induced production of IL-1, IL-6, IL-8, and TNF-in a dose-dependent manner. It also suppressed LPS-induced NF-B activation mediated by TLR4. Moreover, the anti-inflammatory effects of quercetin were reversed by the PPAR-antagonist of GW9662. In conclusion, these results suggested that quercetin attenuated the production of IL-1, IL-6, IL-8, and TNF-inLPS-treated HGFs by activating PPAR-which subsequently suppressed the activation of NF-B.

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