Combination Of Quercetin Research Articles

THE POSSIBLE PROTECTIVE EFFECT OF ZINC, QUERCETIN, OR THEIR COMBINATION ON LEAD-INDUCED NEPHROTOXICITY IN MALE ALBINO RATS: A LIGHT AND TRANSMISSION ELECTRON MICROSCOPIC STUDY

Lead (Pb)-induced nephrotoxicity has been recognized as a human major public health problem. The aim of the present study is to investigate the possible protective effects of zinc (Zn) or/and quercetin on Pb-induced histologic and ultrastructural changes in the rat kidney. For this purpose, 35 adult male albino rats (Rattus norvegicus) were divided equally into 5 groups, each of 7 rats. Group I (control group): rats received physiological saline intraperitoneally (i.p.) and distilled water orally for 14 consecutive days. Group II (Pb-treated group): rats were orally administered lead nitrate (20 mg/kg body weight/day) for 14 consecutive days. Groups III (Zn and Pb-treated group): rats were administered zinc chloride (2 mg/kg body weight/day, i.p.) 1 hour prior to Pb administration, for 14 consecutive days. Group IV (quercetin and Pb-treated group): rats were orally administered quercetin (50 mg/kg body weight/day), 1 hr prior to Pb administration, for 14 consecutive days. Group V (Zn-quercetin and Pb-treated group): rats received Zn, quercetin and Pb at the same doses, periods and ways of administration mentioned above. The kidney structure of Pb-treated rats revealed swollen, congested glomeruli, adhesion of the glomerular tufts to Bowman’s capsules and obliteration of the urinary spaces. Obliteration of the lumina of many glomerular capillary loops was also seen. Some of the renal tubules (mainly the proximal tubules) exhibited luminal dilatation with flattening of their lining epithelial cells, while the other tubules appeared swollen and necrotic with pyknotic or karyolytic nuclei. Exfoliated damaged epithelial cells were also observed within the tubules’ lumina. Interstitial inflammatory cell infiltration, intertubular haemorrhage and an increase in the number of fibroblasts were also detected in the degenerated tissue. Ultrastructurally, Malpighian corpuscles showed electron-dense nuclei of the parietal and endothelial cells, complete fusion and effacement of some foot processes of the podocytes, focal thickening of the glomerular basement membrane and an increase in the number of mesangial cells. Many proximal convoluted tubules revealed apoptotic cells with marginal condensed chromatin of their nuclei, fused distorted mitochondria, increased lysosomes, multiple cytoplasmic vacuoles, destructed microvilli of the brush border, and dilated basolateral invaginations. However, simultaneous administration of Zn or quercetin plus Pb partially protected the renal tissues against the toxic effects of lead. On the other side, the combination of Zn and quercetin offers additional protective effects against Pb-induced nephrotoxicity in rats. It is concluded from the present study that co-treatment with Zn and quercetin has a better renoprotective effect than that induced by Zn or quercetin alone.

Inhibitory Effects of Quercetin on Progression of Human Choriocarcinoma Cells Are Mediated Through PI3K/AKT and MAPK Signal Transduction Cascades.

As a major dietary flavonol, quercetin mitigates proliferation and progression of cancer due to its anti-angiogenic, anti-inflammatory, anti-oxidant, and apoptotic biological effects on cells. Although its apoptotic effects have been reported for various cancers, little is known of the functional role of quercetin in gestational choriocarcinoma. Results of the present study indicated that quercetin reduced proliferation and induced cell death in two choriocarcinoma cell lines, JAR and JEG3 cells, with an increase in the sub-G1 phase of the cell cycle. In addition, quercetin induced mitochondrial dysfunction significantly reduced mitochondrial membrane potential (MMP) and increased production of reactive oxygen species (ROS) in both JAR and JEG3 cells. Further, quercetin inhibited phosphorylation of AKT, P70S6K and S6 proteins whereas, it increased phosphorylation of ERK1/2, P38, JNK and P90RSK proteins in JAR and JEG3 cells. The decrease in viability of choriocarcinoma cells treated with quercetin was confirmed by using combinations of quercetin and pharmacological inhibitors of the PI3K and MAPK signaling pathways. Classical chemotherapeutic agents, cisplatin (a platinum-based drug) and paclitaxel (a taxene-based drug), inhibited proliferation of JAR and JEG3 cells, and when combined with quercetin, the antiproliferative effects of cisplatin and paclitaxel were enhanced for both choriocarcinoma cell lines. Collectively, these results suggest that quercetin prevents development of choriocarcinoma and may be a valuable therapeutic agent for treatment of choriocarcinoma through its regulation of PI3K and MAPK signal transduction pathways. J. Cell. Physiol. 232: 1428-1440, 2017. © 2016 Wiley Periodicals, Inc.

A combination of resveratrol and quercetin induces browning in white adipose tissue of rats fed an obesogenic diet.

To analyze whether a combination of quercetin (Q) and resveratrol (RSV) would induce a white adipose tissue (WAT) browning effect. Thirty-six rats were fed an obesogenic diet and divided into four groups: control, treated with RSV (15 mg/kg body weight/day; RSV group), treated with Q (30 mg/kg body weight/day; Q group), or treated with both polyphenols (RSV + Q group). After 6 weeks, body and WAT weights were significantly reduced in the RSV + Q group. In perirenal WAT of the control, RSV, and Q groups, white unilocular adipocytes appeared in the majority of cells, while in the RSV + Q group numerous multilocular adipocytes with positive immunostaining for UCP1 were observed. The presence of UCP1 was confirmed by Western blot. This group also revealed increased mRNA levels of Cidea, Hocx9, Bmp4, Slc27a1, Pat2, Atgl, and Atp5d. Interscapular brown adipose tissue weight showed no differences between groups, but the Cidea mRNA level was increased in the RSV group, the Cox-2 mRNA level in the RSV + Q group, and UCP1 protein expression in the RSV and the RSV + Q groups. This study demonstrated that the RSV + Q combination produces a brown-like remodeling effect in perirenal WAT, as well as increased UCP1 protein expression in interscapular brown adipose tissue.

Effects of Luteolin and Quercetin in Combination with Some Conventional Antibiotics against Methicillin-Resistant Staphylococcus aureus.

The present study was designed to evaluate the effects of flavonoids luteolin (L) and quercetin + luteolin (Q + L) in combination with commonly used antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates and S. aureus (ATCC 43300). Minimum inhibitory concentrations (MICs) of L and Q + L, as well as the MICs of flavonoids in combination with antibiotics were determined and results showed an increased activity of flavonoids with antibiotics. The synergistic, additive, or antagonistic relationships between flavonoids (L and Q + L) and antibiotics were also evaluated, and additive and synergistic effects were observed for some antibiotic + flavonoid combinations. In addition, some combinations were also found to damage the bacterial cytoplasmic membrane, as assessed through potassium leakage assay. The effects of flavonoids and flavonoids + antibiotics on mecA gene mutations were also tested, and no functional variation was detected in the coding region.

Plant growth regulator-mediated anti-herbivore responses of cabbage (Brassica oleracea) against cabbage looper Trichoplusia ni Hübner (Lepidoptera: Noctuidae)

Plant elicitors can be biological or chemical-derived stimulators of jasmonic acid (JA) or salicylic acid (SA) pathways shown to prime the defenses in many crops. Examples of chemical elicitors of the JA and SA pathways include methyl-jasmonate and 1,2,3-benzothiadiazole-7-carbothioate (BTH or the commercial plant activator Actigard 50WG, respectively). The use of specific elicitors has been observed to affect the normal interaction between JA and SA pathways causing one to be upregulated and the other to be suppressed, often, but not always, at the expense of the plant's herbivore or pathogen defenses. The objective of this study was to determine whether insects feeding on Brassica crops might be negatively affected by SA inducible defenses combined with an inhibitor of detoxification and anti-oxidant enzymes that regulate the insect response to the plant's defenses. The relative growth rate of cabbage looper Trichoplusia ni Hübner (Lepidoptera: Noctuidae) fed induced cabbage Brassica oleraceae leaves with the inhibitor, quercetin, was significantly less than those fed control cabbage with and without the inhibitor. The reduced growth was related to the reduction of glutathione S-transferases (GSTs) by the combination of quercetin and increased levels of indole glucosinolates in the cabbage treated with BTH at 2.6× the recommended application rate. These findings may offer a novel combination of elicitor and synergist that can provide protection from plant disease and herbivores in cabbage and other Brassica crops.

Efficacy of an orally administered combination of hyaluronic acid, chondroitin sulfate, curcumin and quercetin for the prevention of recurrent urinary tract infections in postmenopausal women

ObjectiveTo assess whether the orally administered combination of hyaluronic acid (HA), chondroitin sulfate (CS), curcumin and quercetin could be effective in preventing recurrent cystitis in postmenopausal women and whether its efficacy was conditioned by the concurrent use of local estrogen therapy. Study designThis was a prospective evaluation of 145 postmenopausal women consecutively recruited from the database of three different investigators. All women should have mild-to-moderate urogenital atrophy and a history of recurrent urinary tract infections (≥2 episodes within 6 months or ≥3 episodes within 12 months documented by positive urine cultures) during the last year. Patients were assigned to three different therapeutic regimens: the first group was treated only with vaginal estrogens, the second group only with HA, CS, curcumin and quercetin per os, and the third group was treated with HA, CS, curcumin and quercetin associated with local estrogens. We evaluated the number of patients with <2 infective episodes in the 6-month follow-up and <3 episodes in the 12-month follow-up (main aim definition) and the reduction of related symptoms through a Visual Analog Scale (VAS) and the Pelvic Pain and Urgency/Frequency (PUF) patient symptom scale. Student's t-test and chi-squared test were used for data analysis as appropriate. ResultsAt 6-month follow up, the main aim rate was 8%, 11.1% and 25% in the three groups, respectively (p<0.05 compared to baseline only in group 3). Although the reduction in the number of recurrent episodes became significant in all groups at 1 year follow-up, the main aim rate was almost double in women receiving both local estrogens and oral therapy (group 3) compared to those receiving single treatments. The improvement of related symptoms was significant in all groups at 12-month follow-up. ConclusionsIn postmenopausal women, the combination of HA, CS, curcumin and quercetin per os was effective in preventing recurrent urinary tract infections, especially if administered with vaginal estrogen therapy.

Quercetin and Cisplatin combined treatment altered cell cycle and mitogen activated protein kinase expressions in malignant mesotelioma cells.

BackgroundMalignant mesothelioma is a locally aggressive and highly lethal neoplasm of pleural, peritoneal and pericardial mesothelial cells without successful therapy. Previously, we reported that Quercetin in combination with Cisplatin inhibits cell proliferation and activates caspase-9 and -3 enzymes in different malignant mesothelioma cell lines. Moreover, Quercetin + Cisplatin lead to accumulation of both SPC111 and SPC212 cell lines in S phase.MethodsIn present work, 84 genes involved in cell growth and proliferation have analysed by using RT2-PCR array system and protein profile of mitogen activated protein kinase (MAPK) family proteins investigated by western blots.ResultsOur results showed that Quercetin and Quercetin + Cisplatin modulated gene expression of cyclins, cyclin dependent kinases and cyclin dependent kinases inhibitors. In addition genes involved in JNK, p38 and MAPK/ERK pathways were up regulated. Moreover, while p38 and JNK phosphorylations were increased, ERK phosphorylations were decreased after using Quercetin + Cisplatin.ConclusionThis research has clarified our previous results and detailed mechanism of anti-carcinogenic potential of Quercetin alone and incombination with Cisplatin on malignant mesothelioma cells.

Abstract 260: Quercetin protects from doxorubicin induced vascular toxicity but impairs its cytotoxic profile in breast cancer cells

Abstract The use of anti-cancer adjuvant therapy is rationalized by potentiating the efficacy and/or protecting from major side effects of chemotherapeutics. Doxorubicin is an effective anthracycline anticancer agent for breast cancer despite its dose-limiting cardiovascular toxicity. Quercetin is a flavonoid compound with potent antioxidant and cardiovascular protective activity. The purpose of this study is to investigate the influence of quercetin on the cytotoxic profile of doxorubicin in breast cancer cell lines on the top of ameliorating doxorubicin induced acute vascular toxicity. Incubation of isolated aortic rings with doxorubicin (10 uM) significantly increased contractile response of aorta to phenylephrine and decreased its relaxation response to acetylcholine. Quercetin significantly protected from doxorubicin induced vascular toxicity showing reduced contractile and increased relaxation responses of aorta to doxorubicin. On the other hand, quercetin combination significantly resulted in increasing the IC50 of doxorubicin from 0.4±0.03 to 0.8±0.06 μM in MCF-7 cells with combination index indicative of strong antagonism (CI-value = 3.2). The IC50 of doxorubicin did not change after combination with quercetin in MDA-MB-231 cells (70±10 and 76.3±4 nM, respectively), however the CI-value was 1.98 which is indicative of antagonism as well. Only in T47D cells, quercetin combination with doxorubicin was additive (CI-value = 1.17) and the IC50 of doxorubicin was significantly dropped from 0.74±0.05 to 0.36±0.003 μM. Quercetin did not affect total ROS level induced by doxorubicin, however, it significantly impaired the immediate phase of intracellular ROS generation by doxorubicin within MCF-7 cells from 125.2±3.6% to 102.5±3.9% of control cells. Yet, quercetin synergized doxorubicin cytotoxicity against MCF7 cells under hypoxic condition and significantly decreased its IC50 from 8.9±0.7 to 0.9±0.02 μM (CI-value = 0.2). Further investigation showed that the combination of doxorubicin with quercetin significantly increased the concentration of pro-caspase 3 compared to doxorubicin alone in T47D and MDA-MB-231 cell lines. Cell death mechanism was further investigated using annexin-V/PI differential staining. Quercetin combination did not significantly increase the percent of apoptotic or necrotic cells compared to treatment with doxorubicin alone in all cell lines under investigation. In addition, quercetin induced significant accumulation of cells at S-phase as well as in G2/M-phase in both MCF-7 and MDA-MB-231 cell lines. Quercetin did not affect cell cycle distribution in T47D cells. In conclusion quercetin despite its potent vascular protective activity against doxorubicin, it shows antagonistic to boarder line-additive interactions with doxorubicin in different breast cancer cell lines. Citation Format: Hanan A. Assiri, Fahad A. Al-Abbasi, Hany M. El-Bassossy, Mohamed A. El-Moselhy, Ahmed M. Al-Abd. Quercetin protects from doxorubicin induced vascular toxicity but impairs its cytotoxic profile in breast cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 260.

Enhanced anti-inflammatory effects of DHA and quercetin in lipopolysaccharide-induced RAW264.7 macrophages by inhibiting NF-κB and MAPK activation.

The aim of the present study was to investigate the anti-inflammatory effects of docosahexaenoic acid (DHA)+quercetin (QE) used in combination. DHA and QE are natural compounds derived from various foods and have been demonstrated to exert anti‑inflammatory effects The protein mRNA expression involved in the nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signalling pathway was analyzed by western blot analysis and reverse transcription-polymerase chain reaction methods respectively, other cytokines were detected by an enzyme‑linked immunosorbent assay kit. The results of the present study demonstrated that combined treatment of lipopolysaccharide (LPS)‑stimulated RAW264.7cells with DHA+QE decreased the levels of pro‑inflammatory mediators to a greater extent than QE or DHA alone. Additionally, DHA+QE synergistically suppressed nitric oxide, prostaglandinE2 and cyclooxygenase-2 levels. Molecular‑level studies indicated that the DHA+QE combination can significantly inhibit the mRNA expression of NF‑κB subunits p50 and p65, extracellular signal‑regulated kinase (ERK)1/2 and c‑JUN N‑terminal kinase (JNK)1/2, which suggests that the NF‑κB signalling pathway is involved in the synergistic effects observed. Furthermore, western blot analysis demonstrated that DHA+QE synergistically inhibit the phosphorylation of p50, p65, ERK1/2 and JNK1/2. This finding indicates that the enhanced anti‑inflammatory effects of the combined compounds are achieved by suppressing NF‑κB and MAPK signalling in LPS‑stimulated RAW264.7cells. The results of the present study suggest that DHA and QE in combination may be utilized as potent anti‑inflammatory compounds, with potential preventative or palliative effects on obesity, atherosclerosis and cardiovascular diseases.

Quercetin blocks t-AUCB-induced autophagy by Hsp27 and Atg7 inhibition in glioblastoma cells in vitro.

We previously demonstrated that the acquired resistance because of Hsp27 activation weakens the cytotoxic effect of t-AUCB on glioblastoma cells. Since autophagy is regarded as a survival mechanism for cells exposed to cytotoxic agents, the aim of this study is to investigate whether t-AUCB induces autophagy and whether Hsp27 and autophagy are interacted with each other. Our data demonstrated that t-AUCB induces autophagy in glioblastoma cells and regulates multiple autophagy related-gene expression. t-AUCB induces overexpression of Atg7, which is downstream of Hsp27 and participates in the resistance of glioblastoma cells to t-AUCB treatment. Hsp27 inhibitor quercetin suppresses Atg7 expression and strengthens t-AUCB-induced cell death by autophagy blockage. We concluded that combination of quercetin and t-AUCB might be a potential strategy for glioblastoma treatment.

Quercetin and rutin as potential agents antifungal against Cryptococcus spp.

Amphotericin B is a fungicidal substance that is treatment of choice for most systemic fungal infections affecting as cryptococcosis the immunocompromised patients. However, severe side effects have limited the utility of this drug. The aim of this study was to evaluate the antifungal effect of the combination of amphotericin B with quercetin or rutin and as a protective of citotoxic effect. The antifungal activity to amphotericin B, quercetin and rutin alone and in combination was determined in Candida sp and Cryptococcus neoformans strains. Cytotoxicity test on erythrocytes was performed by spectrophotometric absorbance of hemoglobin. The amphotericin B MIC was reduced when used in combination with quercetin or rutin to C. neoformans ATCC strain and reduced when combined with rutin to a clinical isolate of C. neoformans. In addition, the combination of quercetin with amphotericin B may reduce the toxicity of amphotericin B to red blood cells. Our results suggest that quercetin and rutin are potential agents to combine with amphotericin B in order to reduce the amphotericin dose to lessen side effects and improve antifungal efficacy.

Quercetin sensitizes glioblastoma to t-AUCB by dual inhibition of Hsp27 and COX-2 in vitro and in vivo.

BackgroundEvidences indicate that inflammatory process plays pivotal role in tumor disease. Soluble epoxide hydrolase inhibitors (sEHIs) have been shown to participate in anti-inflammation and tumorigenesis by protecting epoxyeicosatrienoic acids (EETs). Although we have previously revealed some effects of t-AUCB on glioma in vitro, further investigations are needed to demonstrate its effects on glioblastoma growth in vivo and how to strengthen its antitumor effect.MethodsCCK-8 kit was used to test cell growth. Cell migration capacity was performed by wound healing assays. Transwell assay was used to test cell invasion potency. Cell-cycle analysis and cell apoptosis was performed by flow cytometry. The activity of caspase-3 in cells was measured using caspase-3 activity assay kits. Total RNA was extracted from cells lysated by TRIzol reagent. qRT-PCR was performed by ABI 7500 fast RT- PCR system. Lipofectamine RNAiMAX Transfection Reagent (Invitrogen) was used for siRNA transfection. Western blootting was used to test protein expression. Tumor cell xenograft mouse models were used for in vivo study. The SPSS version 17.0 software was applied for statistical analysis.ResultsOur data shown that t-AUCB inhibits cell proliferation, migration and invasion and induces cell cycle G1 phase arrest in vitro but induces no cell apoptosis; increased Hsp27 activation and following COX-2 overexpression confer resistance to t-AUCB treatment in glioblastoma both in vitro and in vivo; quercetin sensitizes glioblastoma to t-AUCB by dual inhibition of Hsp27 and COX-2 in vitro and in vivo.ConclusionsThese results indicate that combination of t-AUCB and quercetin may be a potential approach to treating glioblastoma.

PHARMACODYNAMIC INTERACTION OF QUERCETIN AND SILYMARIN AGAINST CYCLOPHOSPHAMIDE INDUCED CARDIO-TOXICITY

The study was designed to investigate the cardioprotective effect of different combination of Silymarin and Quercetin against Cyclophosphamide induced cardiotoxicity in experimental rats . The Albino rats of either sex were divi ded into five groups of six animals . Group 1 and group 2 served as normal and control group respectively . Other groups treated with Silymarin ( 60 mg / kg, p . o . ) alone, high ( 30 mg / kg, p . o . ) and low ( 15 mg / kg, p . o . ) dose of Silymarin combined with Quercetin ( 10 mg / kg, p . o .). Myocardial damage was induced by the administration of Cyclophosphamide ( 200mg / kg, i . p . ) on the first day and the treatment was conducted for ten days . Twenty - four hours after the last administration, the blood was collected by the retro - o rbital puncture method and the serum biomarker level of Lactate Dehydrogenase ( LDH ) , Creatinine Kinase - NAC ( CK - NAC ) , Creatinine Kinase - MB ( CK - MB ) , Aspartate Transaminase ( AST ) , Alanine Transaminase ( ALT ) and Alkaline Phosphatase ( ALP ) in serum were evaluat ed . Electro - cardiograph parameters such as Heart rate, QRS interval, QT segment, PR interval and RR interval also carried out . Compared to the control group all treated group showed significant activity and high and low dose combination group showed profou nd car diac protection compare to the S ilymarin alone . Among the entire groups high dose combination group ( SILLY30 + QUE10 ) showed most effective Cardio - protection and was also responsible for the significant improvement in the ECG parameters .

New Treatment of Medullary and Papillary Human Thyroid Cancer: Biological Effects of Hyaluronic Acid Hydrogel Loaded With Quercetin Alone or in Combination to an Inhibitor of Aurora Kinase.

The aim of this paper is based on the use of a hyaluronic acid hydrogel of Quercetin tested alone and in combination to an inhibitor of Aurora Kinase type A and B (SNS-314) on human medullary and papillary thyroid cancer cells. Biological investigations were focused on the cellular uptake of the hydrogel, cell viability, antioxidant, and cytokines secretion studies. Quercetin delivered from hydrogel show a time and CD44 dependent interaction with both cell lines with significant anti-inflammatory effects. Combination of Quercetin and SNS-314 leads to a synergistic cytotoxic effect on medullary TT and papillary BCPAP cell lines with a significant reduction of the IC50 value. These results, highlights the importance of synergistic effect of the hyaluronic acid hydrogel of Quercetin with SNS-314 in the regulation of human thyroid cancer cell proliferation and emphasize the anti-tumor activity of these molecules. J. Cell. Physiol. 231: 1784-1795, 2016. © 2015 Wiley Periodicals, Inc.

Effect of 2-methoxyestradiol combined with quercetin on prostate cancer in vitro

To detect the effects of quercetin (Que) combined with 2-methoxyestradiol (2-ME) on the proliferation of androgen-dependent LNCaP human prostate cancer cells line and androgen-independent PC-3 human prostate cancer cells line, and to evaluate the antitumor effects of different combos of the two drugs. After LNCaP and PC-3 cells were treated with different concentration of quercetin (0, 3.125, 6.25, 12.5, 25, 50, 100, 200 μmol/L) or 2-ME (0, 0.312 5, 0.625, 1.25, 2.5, 5, 10 μmol/L) for 48 h, the inhibitory rates of cell growth were tested using trypan blue staining method respectively. Then the concentration-effect curves were drawn and IC(50) values were calculated. According to the fitted dose-effect curves and IC(50) values, appropriate concentrations of quercetin and 2-ME were selected to compose 16 different combos. Then cells were treated with different combos of Que and 2-ME for 48 h, and then the growth inhibitory rates of cell growth were detected. According to the equation and median-effect principle, the CI values of 16 different combos of Que and 2-ME were calculated to evaluate their antitumor effects. The inhibition rate of LNCaP or PC-3 cell growth treated with varying doses of quercetin or 2-ME alone showed a dose-dependent increase respectively. The IC(50) values of quercetin and 2-ME were 23.29 μmol/L and 1.89 μmol/L for LNCaP cells; and 22.12 μmol/L and 1.74 μmol/L for PC-3 cells respectively. After treated with 16 combos of Que (5, 10, 20, 40 μmol/L) and 2-ME (0.5, 1, 3, 5 μmol/L) for 48 h, for LNCaP cells, lower dose of Que (5 and 10 μmol/L) with higher dose of 2-ME (3 and 5 μmol/L) showed synergistic activity, whereas for PC-3 cells, besides the above combination of Que 10 μmol/L and 2-ME 3 μmol/L, higher dose of quercetin (20 and 40 μmol/L) with higher dose of 2-ME (3 and 5 μmol/L) also showed synergistic activity. Both quercetin and 2-methoxyestradiol could inhibit the growth of LNCaP and PC-3 human prostate cancer cells in a dose dependent manner. We confirmed that combinations of quercetin and 2-ME at appropriate concentrations have the potential for synergetic antiproliferative activity in vitro.

Enhanced therapeutic efficacy and amelioration of cisplatin-induced nephrotoxicity by quercetin in 1,2-dimethyl hydrazine-induced colon cancer in rats.

Objective:The aim of quercetin treatment in combination of cisplatin (CP)-induced nephrotoxicity as well on 1,2-dimethyl hydrazine (DMH)-induced colon cancer.Materials and Methods:In this study, animals are exposed to DMH hydrochloride to induce colon cancer. In these groups, nephrotoxicity was assessed with the help of blood urea nitrogen, urea, and creatinine. The antitumor activity of quercetin and CP assessed with the help of number of aberrant crypts and foci formation. Tumor size in different treatment group determined with the help of vernier caliper.Results:CP is one of the most widely used antineoplastic drugs against colon cancer, but it has a major dose-limiting drawbacks of causing nephrotoxicity. Therefore, there is a need for a novel therapeutic regimen which will reduce the nephrotoxicity and enhance the anticancer activity of CP. The protective effect of quercetin on CP-induced nephrotoxicity is well-known. Moreover, quercetin is proven to have antitumor activity in colon cancer. Keeping all the facts in view, this study was conceived to evaluate the role of quercetin on therapeutic efficacy and nephrotoxicity of CP in DMH-induced colon cancer in male Sprague–Dawley rats. Treatment of quercetin with CP (7.5 mg/kg) prevents the CP-induced nephrotoxicity along with enhance the anticancer activity confirmed by the reduction of aberrant crypt foci number. Treatment of CP and quercetin alone leads to significant increase in the anticancer activity as compared to control colon tumor rats.Conclusion:In DMH-induced colon cancer model, combination of quercetin and CP ameliorates CP-induced nephrotoxicity as well as enhanced antitumor activity.

Bone health nutraceuticals alter microarray mRNA gene expression: A randomized, parallel, open-label clinical study

Background and objectiveDietary intake of fruits and vegetables has been suggested to have a role in promoting bone health. More specifically, the polyphenols they contain have been linked to physiological effects related to bone mineral density and bone metabolism. In this research, we use standard microarray analyses of peripheral whole blood from post-menopausal women treated with two fixed combinations of plant extracts standardized to polyphenol content to identify differentially expressed genes relevant to bone health. MethodsIn this 28-day open-label study, healthy post-menopausal women were randomized into three groups, each receiving one of three investigational fixed combinations of plant extracts: an anti-resorptive (AR) combination of pomegranate fruit (Punica granatum L.) and grape seed (Vitis vinifera L.) extracts; a bone formation (BF) combination of quercetin (Dimorphandra mollis Benth) and licorice (Glycyrrhiza glabra L.) extracts; and a fixed combination of all four plant extracts (AR plus BF). Standard microarray analysis was performed on peripheral whole blood samples taken before and after each treatment. Annotated genes were analyzed for their association to bone health by comparison to a gene library. ResultsThe AR combination down-regulated a number of genes involved in reduction of bone resorption including cathepsin G (CTSG) and tachykinin receptor 1 (TACR1). The AR combination also up-regulated genes associated with formation of extracellular matrix including heparan sulfate proteoglycan 2 (HSPG2) and hyaluronoglucosaminidase 1 (HYAL1). In contrast, treatment with the BF combination resulted in up-regulation of bone morphogenetic protein 2 (BMP-2) and COL1A1 (collagen type I α1) genes which are linked to bone and collagen formation while down-regulating genes linked to osteoclastogenesis. Treatment with a combination of all four plant extracts had a distinctly different effect on gene expression than the results of the AR and BF combinations individually. These results could be due to multiple feedback systems balancing activities of osteoblasts and osteoclasts. ConclusionIn summary, this ex-vivo microarray study indicated that the pomegranate, grape seed, quercetin and licorice combinations of plant extracts modulated gene expression for both osteoclastic and osteogenic processes.

Quercetin Displays Anti-Myeloma Activity and Synergistic Effect with Dexamethasone in Vitro and In Vivo Xenograft Models

Background: Multiple myeloma (MM) is a hematological malignancy with clonal plasma cell hyperplasia, which is still an incrurable disease since chemoresistance remains the major problem in MM management. Quercetin, a kind of dietary flavonoids, has shown its anticancer activity in many kinds of cancer cell lines and we tried to explore the effect of quercetin in MM.Methods: In vitro, we examined the proliferation of MM cell lines(RPMI8226,ARP-1,MM1R) after treatment with quercetin combined with or without dexamethasone by MTT.Flow cytometry was used to detect apoptosis and cell cycle of MM cells induced by quercetin with or without dexamethasone.Then we detected mRNA and protein expression associated with apoptosis and cell cycle arrest by semiquantitative real time-polymerase chain (qRT-PCR)and western blot analysis. In vivo,a xenograft mice model of human myeloma was established and the mice received vehicle or quercetin alone or dexamethasone alone or quercetin combinded with dexamethasone, and the tumorburdern and the tumor tissue samples were analyzed by tumor volume and immunohistochemistry.Results: Quercetin inhibited proliferation of MM cells by inducing apoptosis and cell cycle arrest in the G0/G1 or G2 phase(quercetin group vs control,p<0.05).Western blot showed that quercetin activated caspase3,caspase9,PARP-1 and increased cytochrome C release. C-myc and cyclinD1 expression were down-regulated and p21 were upregulated. Quercetinalso displays synergistic inhibition effect with dexamethasone in vitro (quercetin with dexamethasone vs quercetin only or dexamethasone only,p<0.05) and western bolt confirmed these results.In vivo,tumor burdern of xenograft mice modeltreated by quercetin was significantly lower than those of control(quercetin group vs control,p<0.05).Conclusions: Quercetin inhibits proliferation of MM cells by inducing apoptosis and cell cycle arrest in the G0/G1 or G2 phase through downregulating c-myc and cyclinD1 and upregulating p21 .Quercetinalso displays synergistic inhibition effect with dexamethasone.Thus,quercetin combination with dexamethasone therapy may be an effective option for MM patients. DisclosuresNo relevant conflicts of interest to declare.

Suppression of HSP27 increases the anti‑tumor effects of quercetin in human leukemia U937 cells.

Quercetin, a natural flavonoid, inhibits the growth of leukemia cells and induces apoptosis. Heat shock protein 27 (HSP27) has been reported to promote the development of leukemia by protecting tumor cells from apoptosis through various mechanisms. The present study investigated the effects of small hairpin (sh)RNA-mediated HSP27 knockdown on the anti-cancer effects of quercetin in U937 human leukemia cells. Cells were transfected with recombinant lentiviral vector pCMV-G-NR-U6-shHSP27 (shHSP27), which expressed shRNA specifically targeting the HSP27 gene, alone or in combination with quercetin. The results showed that shHSP27 and quercetin synergistically inhibited U937 cell proliferation and induced apoptosis by decreasing the Bcl2-to-Bax ratio. Furthermore, this combined treatment significantly suppressed the infiltration of tumor cells and the expression of angiogenesis-associated proteins HIF1α and VEGF. Compared with shHSP27 or quercetin alone, shHSP27 plus quercetin markedly decreased the protein expression of cyclinD1 and thus blocked the cell cycle at G1 phase. The Notch/AKT/mTOR signaling pathway is important in tumor aggressiveness; quercetin plus shHSP27 significantly decreased Notch 1 expression and the phosphorylation levels of the downstream signaling proteins AKT and mTOR. The inhibitory effects of quercetin plus shHSP27 on this pathway may thus have been responsible for the cell cycle arrest, inhibition of proliferations and infiltration as well as enhancement of apoptosis. Therefore, these findings collectively suggested that suppression of HSP27 expression amplified the anti-cancer effects of quercetin in U937 human leukemia cells, and that quercetin in combination with shHSP27 represents a promising therapeutic strategy for human leukemia.

Quercetin Mediates β-Catenin in Pancreatic Cancer Stem-Like Cells.

The aim of this study is to explore how quercetin interacts with pancreatic cancer stem-like cells and the mechanism underlying the effective quercetin-mediated suppression. A model of pancreatic cancer stem-like cells was generated by using a sphere formation culture system. A comparative analysis was performed between the parent cells and pancreatic cancer stem-like cells with a related treatment strategy focusing on cancer stem cell (CSC) properties and drug-resistance-related mechanisms in vitro. Our data show that pancreatic cancer stem-like cells have greater resistance to gemcitabine and stronger CSC properties compared with the parent cells. In contrast to the pancreatic cancer stem-like cells, overexpression of β-catenin was observed in the parent cells. Quercetin suppressed proliferation, invasion and self-renewal capacity, and CSC surface markers expression, with alterations of β-catenin in pancreatic cancer stem-like cells. The combination of quercetin and gemcitabine can reduce tumor growth and decrease drug resistance in pancreatic cancer. β-Catenin plays an important role in maintenance and progression of pancreatic cancer. Targeting β-catenin using quercetin combined with gemcitabine may be a treatment strategy to improve prognosis in patients with pancreatic cancer.