PMID: 

Artif Cells Nanomed Biotechnol. 2019 Dec ;47(1):3265-3271. PMID: 31368817

Abstract Title: 

Luteolin exhibits anti-breast cancer property through up-regulating miR-203.

Abstract: 

Luteolin is a representative of natural flavonoid that has anti-tumour properties. This study designed to check its impact on breast cancer and the underlying mechanisms. MDA-MB-453 and MCF-7 cells were administrated with luteolin and the following techniques were carried out: CCK-8 assay, FITC-PI double-staining and Western blot. qRT-PCR analysis was utilized to see the effects of luteolin on miR-203 expression. Besides, miR-203 expression was silenced by transfection with specific inhibitor. Luteolin remarkably declined MDA-MB-453 and MCF-7 cells viability and accelerated apoptosis which accompanied by Bax up-regulation, Bcl-2 down-regulation and Caspase-3 cleavage. Also, luteolin impeded TGFβ1-induced EMT, as evidenced by the decreased levels of Vimentin, Zeb1 and N-cadherin, as well as the increased level of E-cadherin. miR-203 was highly expressed in 22 pair of breast cancer tissues than the matched paracancerous tissues. Luteolin could elevate miR-203 level. Besides, luteolin's anti-tumour effects were partially eliminated by miR-203 silence. Further, luteolin inhibited Ras/Raf/MEK/ERK signalling, while the inhibitory effects were flattened by miR-203 silence. Luteolin significantly reduced breast cancer cells growth and EMT. Luteolin exerted its anti-tumour effects possiblyinvolved the elevated expression of miR-203 and the inhibited Ras/Raf/MEK/ERK signalling.

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PMID: 

J Surg Res. 2019 Oct 10 ;246:213-223. Epub 2019 Oct 10. PMID: 31606511

Abstract Title: 

Quercetin Promotes Diabetic Wound Healing via Switching Macrophages From M1 to M2 Polarization.

Abstract: 

BACKGROUND: For patients with diabetes mellitus, excessive and long-lasting inflammatory reactions at the wound site commonly lead to the delayed refractory wound healing. The polarization of macrophages in terms of M1 and M2 phenotypes is closely related to the production of inflammatory cytokines. Quercetin is traditionally recognized to have anti-inflammatory effect; however, whether quercetin modulates macrophage polarization from M1 to M2 and thus promotes diabetic wound healing remain unknown.MATERIALS AND METHODS: Wounded male diabetic rats were equally divided into five groups: model group, solvent control group (10% DMSO), and three drug groups treated with quercetin (Q) at concentrations of 10 mg/mL (Q-LD [low dose]), 20 mg/mL (Q-MD ), and 40 mg/mL (Q-HD [high dose]), respectively. The anti-inflammatory effect of quercetin on diabetic wounds was observed. Immunohistochemistry and quantificational real-time polymerase chain reaction were applied to test the changes in macrophage polarization and inflammatory responses.RESULTS: The wound contraction was fastest in Q-HD group. Hematoxylin and eosin (H&E) and Masson's trichrome staining revealed that fibroblast distribution and collagen deposition in quercetin-treated groups were significantly higher than those in the model group. Immunohistochemistry tests showed more CD206-positive cells and less iNOS-positive cells in quercetin-treated groups. Furthermore, the levels of proinflammatory factors in quercetin-treated groups were lower than those in the model group, whereas the levels of the anti-inflammatory factors and angiogenesis-related factors were relatively higher.CONCLUSIONS: In short, quercetin inhibits inflammatory reactions via modulating macrophage polarization switching from M1 to M2 phenotype, thereby accelerating the diabetic wound repair.

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PMID: 

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2019 Oct ;27(5):1409-1415. PMID: 31607291

Abstract Title: 

[Effect of Quercetin on Wnt/β-Catenin Signal Pathway of K562 and K562R Cells].

Abstract: 

OBJECTIVE: To investigate the effect of Quercetin (Qu) on cell proliferation, apoptosis and cell cycle, as well as the expression changes of Wnt/β-catenin signaling pathway, apoptosis and cell cycle regulators and BCR-ABL in CML susceptible cells K562 and imatinib-resistant cells (IM) K562R.METHODS: The trypan blue staining was used to detect the all proliferation. The cell cycle and apoptosis were detected by flow cytometry. The fluorescence quantitative PCR and Western blot were used to detect the expression of mRNA and protein respectively.RESULTS: After administration with 5, 10, 20, 40, 80, 160, 320μmol/L Qu, the inhibition ratio in K562 cells was 5.07%, 5.98%, 11.09%, 31.88%, 56.89%, 70.44%, 86.63%; and that in K562R cells were 4.99%, 9.75%, 10.54%, 8.93%, 25.13%, 46.89%, 68.60%; ICof K562 and K562R was 76.4μmol/L and 230.2 μmol/L, respectively. Flow cytometry showed that Qu (50, 100 and 200 μmol/L) could induce cell apoptosis and cell cycle arrest in a dose-dependent manner (r=0.9914, r=0.9871 respectively). After treatment with Qu (100 μmol/L)，the expressions of mRNA (P＜0.05) and protein(except Caspase-9) expression of Caspase-3, 8 and 9, p21 and p27 increased in K562 cells as compared with control, but the protein expression of p27 and Caspase-3 not changed in K562R. Qu (100 μmol/L) could decrease the mRNA(P＜0.05) and protein levels of Wnt/β-catenin signaling pathway members GSK-3β, β-catenin, Lef-1 and the downstream targets PPAR-δ and Cyclin D1 compared with control. The PCR results showed that Qu could reduce the BCR-ABL mRNA expression in CML cells, but the protein expression of BCR-ABL and p-BCR-ABL not obviouly changed.CONCLUSION: Qu can inhibit the proliferation K562 and K562R cells, and decrease the drug resistance and increase the sensitivity, that relate with inhibiting Wnt/β-catenin signaling pathway, activating apoptosis pathway and cyclins.

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PMID: 

Life Sci. 2019 Oct 12:116933. Epub 2019 Oct 12. PMID: 31614146

Abstract Title: 

Beyond its antioxidant properties: Quercetin targets multiple signalling pathways in hepatocellular carcinoma in rats.

Abstract: 

AIMS: Hepatocellular carcinoma (HCC) pathogenesis involves the interplay of multiple signalling pathways. Notch and Hedgehog (Hh) are two major developmental pathways that act in concert to regulate adult cell repair. CK2α -serine-threonine kinase-down-regulation enhanced apoptotic activity and was proven beneficial for HCC patients. Quercetin is a bioactive flavonoid and has been shown to protect against HCC through its antioxidant activity. This study was carried out to elucidate the antineoplastic effect of quercetin through regulating both Notch and Hh pathways, apoptosis, cell proliferation and CK2α activity.MAIN METHODS: Hepatocellular carcinoma was induced in male Sprague Dawley rats by thioacetamide. Quercetin was administered in both protective and curative doses. Parameters of liver function and oxidative stress were assessed. CK2α, Notch and Hh pathways were evaluated using RT-PCR and ELISA. Apoptosis was investigated by detecting caspase-3, caspase-8 and p53. Proliferative and cell cycle markers as cyclin D1 and Ki-67 were detected immunohistochemically.KEY FINDINGS: Quercetin inhibited CK2α and downregulated mRNA and protein expression of Notch1 and Gli2. Quercetin also suppressed caspase-3 expression but not caspase-8. Quercetin elevated p53 expression whereas proliferative and cell cycle markers cyclin D1 and Ki-67 were downregulated. Markers of hepatic cellular integrity such asAST, ALT, ALP, GGT, albumin and bilirubin were significantly ameliorated. This was confirmed by histological examination. Quercetin also alleviated oxidative stress as shown by SOD, GSH, MDA and NO levels.SIGNIFICANCE: We can conclude that in addition to its antioxidant power, quercetin blocked Notch, Hedgehog, regulated the apoptotic and proliferative pathways and inhibited CK2α in HCC.

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PMID: 

Life Sci. 2019 Oct 14:116956. Epub 2019 Oct 14. PMID: 31622607

Abstract Title: 

Rheumatoid arthritis induces enteric neurodegeneration and jejunal inflammation, and quercetin promotes neuroprotective and anti-inflammatory actions.

Abstract: 

AIMS: The aim of our study was to study the pathological mechanisms induced by the rheumatoid arthritis (RA) on the Enteric Nervous System (ENS).MAIN METHODS: We evaluated the effect of the chronic arthritis and its treatment with 50 mg/kg quercetin alone (AQ) and combined with 17.5 mg/kg ibuprofen (AIQ) for 60 days on neurons, glial cells and intestinal wall. Other groups were used: control (C), arthritic (A) and arthritic treated with 17.5 mg/kg ibuprofen (AI). After 60 days, the jejunum was removed and processed for immunohistochemical techniques. Immunostainings were performed for HuC/D and S100 (myenteric and submucosal plexuses), and GFAP (only myenteric plexus), while immunolabeling for CD45 and CD20 lymphocytes was performed using cryosections. Western blot was performed for GDNF, S100 and GFAP.KEY FINDINGS: A group yielded a remarkable density decrease of the neurons and glial cells with morphometric changes in the myenteric and submucosal plexuses, reduction of the GDNF expression and GFAP-related parameters (GFAP expression, occupancy area and GFAP-expressing glial cells) and intestinal inflammation and atrophy of the mucosa and intestinal wall. AQ group substantially reversed most of these effects, except for intestinal atrophy of the jejunum. The AI and AIQ groups displayed lower beneficial results than AQ for parameters related to the neurons and glial cells, although AIQ did not prevent the inflammation of the mucosa.SIGNIFICANCE: The severe chronic rheumatoid arthritis induced severe effects on ENS and mucosa, and quercetin treatment continues to be an important antioxidant supplement preventing the progression of the RA severity.

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PMID: 

Food Chem. 2019 Dec 15 ;301:125295. Epub 2019 Jul 30. PMID: 31387038

Abstract Title: 

The effects of organic and conventional farm management and harvest time on the polyphenol content in different raspberry cultivars.

Abstract: 

Raspberry fruits are a perfect source of polyphenols, including flavonols, anthocyanins. Some experiments have indicated that organic fruits contain more bioactive compounds than conventional fruits. The aim of this study was therefore to analyse and compare the concentration of bioactive compounds in organic vs. conventional raspberries and to determine the effects of harvest time and cultivar. Three cultivars of raspberry ('Laszka', 'Glen Ample' and 'Glen Fine') that were harvested in summer and one 'Polka' cv. that was harvested in autumn time from organic and conventional cultivation methods were used in the experiment. The contents of dry matter and polyphenols in the fruits were determined. The organic samples contained significantly more dry matter, phenolic acid and flavonoids, including myrycetin, quercetin, luteolin and quercetin-3-O-rutinoside. Harvest time was an important factor in raspberry fruit quality.

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PMID: 

Biochem Biophys Res Commun. 2019 Oct 1 ;517(4):617-622. Epub 2019 Aug 3. PMID: 31383362

Abstract Title: 

Regulation of apoptosis and autophagy by luteolin in human hepatocellular cancer Hep3B cells.

Abstract: 

In several cancer cells, luteolin (3',4',5,7-tetrahydroxyflavone) exerts anticancer effects by upregulation of oxidative stress and endoplasmic reticulum (ER) stress, which are shown to activate p53-dependent cell death. Since luteolin-mediated ER stress regulation has not been investigated in hepatocellular carcinoma (HCC) cells, we investigated the role of ER stress in anti-carcinogenic effects using p53-wild type and p53-null HCC cells treated with luteolin. Trypan blue exclusion test was implemented to determine cell viability. Western blot was applied to compare the difference of autophagy, apoptosis, and proliferation event between cell lines. ER stress and p53 activation were determined by RT-PCR. Our results showed that luteolin at 5-10 μmol/L induced higher cytotoxicity in p53-null Hep3B cells than in p53-wild type HepG2 cells. Cytotoxicity was not observed in normal liver cells. Apoptosis activation and proliferation inhibition occurred in only p53-null Hep3B cells in response to luteolin treatment. Also, luteolin induced oxidative stress and ER stress in p53-null Hep3B cells. Although we observed the induction of p21 in Hep3B cells, the concomitant increases in mRNA levels of p53 family members, including TAp63 and TAp73, were not observed. Furthermore, luteolin induced autophagy in Hep3B cells only, which enhanced cell viability. Taken together, this study suggests that luteolin-induced ER stress may exert anticancer effects in a p53-independent manner.

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PMID: 

EXCLI J. 2019 ;18:750-763. Epub 2019 Sep 2. PMID: 31611756

Abstract Title: 

Differential effects of luteolin and its glycosides on invasion and apoptosis in MDA-MB-231 triple-negative breast cancer cells.

Abstract: 

Luteolin is known to have anticancer activity in various cancers. Recent studies have shown that luteolin glycosides, such as luteolin-8–β-fucopyranoside, 7-methoxy-luteolin-8-C-β-(6- deoxyxylopyranos-3-uloside) and luteolin-8-C-β-d-glucopyranoside, flavonoids that are present in, exert antimigratory and anti-invasive effects, but no cytotoxic effect in estrogen receptor-positive MCF7 breast cancer cells. In the present study, we further investigated and compared differential effects of luteolin and its glycosides in MDA-MB-231 triple-negative breast cancer cells. Luteolin suppressed the expression of matrix metalloproteinase-9 and inhibited migration and invasion in MDA-MB-231 cells treated with the tumor promotor 12-O-tetradecanoylphorbol-13-acetate at non-cytotoxic concentrations (0, 5, and 10μM). Furthermore, at cytotoxic concentrations (20 and 40 μM), luteolin induced apoptosis via extrinsic and intrinsic pathways in MDA-MB-231 cells. However, luteolin glycosides did not exert any cytotoxic, antimigratory, or anti-invasive effect in MDA-MB-231 cells. In brief, luteolin had both antimetastatic and cytotoxic effects on MDA-MB-231 cells, whereas luteolin glycosides had no effect on this cell line. Taking together the present results and our previous findings on the differential effects of luteolin and its glycosides on MDA-MB-231 and MCF-7 breast cancer cells, luteolin and its glycosides can be suggested as a potential candidate for breast cancer therapy.

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PMID: 

Pestic Biochem Physiol. 2019 Sep ;159:163-172. Epub 2019 Jun 24. PMID: 31400778

Abstract Title: 

Apigenin attenuates edifenphos-induced toxicity by modulating ROS-mediated oxidative stress, mitochondrial dysfunction and caspase signal pathway in rat liver and kidney.

Abstract: 

Edifenphos (EDF) (O-ethyl-S, S-diphenyldithiophosphate) is an organophosphate pesticide that is extensively used as a fungicide in agricultural rice fields. However, EDF accumulated in various agricultural products and caused potential health hazards to human and other living organisms. Therefore, the present study was investigated to evaluate the ameliorative role of apigenin (APG); a natural antioxidant against EDF-induced hepato-renal toxicity in rats. Six groups with five male Wistar rats each, were used for this purpose; these groups included the control group (A) that received corn oil; (B) 10 mg/kg APG; (C) 10 mg/kg EDF; (D) 25 mg/kg EDF; (E) 10 mg/kg APG pretreatment for 1 h then 10 mg/kg EDF; (F) 10 mg/kg APG pretreatment for 1 h then 25 mg/kg EDF for 14 consecutive days. Oral administration of EDF led to disruption of the intracellular antioxidant machinery which cause the generation of intracellular reactive oxygen species (ROS). However, EDF promotes deleterious effects like oxidative stress, DNA damage, reduced mitochondrial membrane potential, generation of ROS production, activation of caspase 3/9 activities and causing hepato-renal histopathological changes. However, the pretreatment of APG ameliorated the EDF-induced oxidative damage and apoptosis, through their antioxidant activity or by directly scavenging free radical property. Overall, these results suggest that EDF exerts oxidative stress, and APG could be a potent dietary anti-oxidant regimen against EDF-induced toxicity.

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PMID: 

Food Chem Toxicol. 2019 Nov ;133:110780. Epub 2019 Aug 23. PMID: 31449894

Abstract Title: 

Dietary Apigenin promotes lipid catabolism, thermogenesis, and browning in adipose tissues of HFD-Fed mice.

Abstract: 

Dietary Apigenin (AP), a natural flavonoid from plants, could alleviate high-fat diet (HFD) induced obesity and its complication. Nonetheless, the direct correlation between dietary AP and their effects in adipose tissues remained unclear. In this study, male C57BL/6 mice were fed with low-fat diet, HFD with or without 0.04% (w/w) AP for 12 weeks. Dietary AP ameliorated HFD induced body weight gain, glucose intolerance, and insulin resistance. Energy expenditure was increased with no influence on energy intake, which indicated us that AP prevented obesity by enhancing energy export. Interestingly, AP activated lipolysis (ATGL/FOXO1/SIRT1) without higher cycling free fatty acids (FFAs). FFAs were consumed by the upregulation of fatty acid oxidation (AMPK/ACC), thermogenesis, and browning (UCP-1, PGC-1α). Additionally, adipose tissue metabolic inflammation (NF-кB, MAPK) was also reduced by AP. Our study proposed that dietary AP could be explored as a new dietary strategy to combat obesity and related insulin resistance.

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