Quercetin Abstracts 3



Quercetin can reduce insulin resistance without decreasing adipose tissue and skeletal muscle fat accumulation.
            (Arias et al., 2014) Download
Quercetin exhibits a wide range of biological functions. The first aim of the present work was to analyze the effects of quercetin on fat accumulation in adipose tissue and glycemic control in rats. Any potential involvement of muscle fatty acid oxidation in its effect on glycemic control was also assessed. Animals were fed a high-fat high-sucrose diet either supplemented with quercetin (30 mg/kg body weight/day), or not supplemented, for 6 weeks. One week before killing, a glucose tolerance test was carried out. Muscle triacylglycerol content, serum glucose, insulin, fructosamine and free fatty acids were measured, and homeostatic model assessment for insulin resistance (HOMA-IR) was calculated. The activities of lipogenic enzymes and lipoprotein lipase in adipose tissue, carnitine palmitoyl transferase-1b (CPT-1b) and citrate synthase in skeletal muscle, and the expression of several genes, ACO, CD36, CPT-1b, PPAR-α, PGC-1α, UCP3, TFAM and COX-2 in skeletal muscle were analyzed. Quercetin caused no significant reduction in body weight or adipose tissue sizes. However, fructosamine, basal glucose and insulin, and consequently HOMA-IR, were significantly reduced by quercetin. No changes were observed in the activity of lipogenic enzymes and lipoprotein lipase. Muscle triacylglycerol content was similar in both experimental groups. The expression of ACO, CD36, CPT-1b, PPAR-α, PGC-1α, UCP3, TFAM and COX-2 remained unchanged. It can be concluded that quercetin is more effective as an anti-diabetic than as an anti-obesity biomolecule. The improvement in insulin resistance induced by this flavonoid is not mediated by a delipidating effect in skeletal muscle.

After cellular internalization, quercetin causes Nrf2 nuclear translocation, increases glutathione levels, and prevents neuronal death against an oxidative insult.
            (Arredondo et al., 2010) Download
In this work we describe the protective effects of quercetin against H(2)O(2) in 24-h-pretreated neuronal cultures. We explored quercetin availability and subcellular fate through the use of HPLC-Diode Array Detection (DAD), epifluorescence, and confocal microscopy. We focused on quercetin modulation of thiol-redox systems by evaluating changes in mitochondrial thioredoxin Trx2, the levels of total glutathione (GSH), and the expression of the gamma-glutamate-cysteine ligase catalytic subunit (GCLC), the rate-limiting enzyme of GSH synthesis, by the use of Western blot, HPLC, and real-time PCR techniques, respectively. We further explored the activation of the protective NF-E2-related factor 2 (Nrf2)-dependent signaling pathway by quercetin using immunocytochemistry techniques. Our results showed rapid quercetin internalization into neurons, reaching the nucleus after its addition to the culture. Quercetin pretreatment increased total GSH levels, but did not increase Trx2. Interestingly it caused Nrf2 nuclear translocation and significantly increased GCLC gene expression. At the moment of H(2)O(2) addition, intracellular quercetin or related metabolites were undetectable in the cultures although quercetin pretreatment prevented neuronal death from the oxidant exposure. Our findings suggest alternative mechanisms of quercetin neuroprotection beyond its long-established ROS scavenging properties, involving Nrf2-dependent modulation of the GSH redox system.

The pro-apoptotic effect of quercetin in cancer cell lines requires ERβ-dependent signals.
            (Bulzomi et al., 2012) Download
Quercetin has potentially beneficial effects on disease prevention, including cancer. An intriguing issue regarding the mechanisms of action of quercetin is the ability of this drug to modulate estrogen receptor (ER) activities. In a previous study, we demonstrated that quercetin elicited apoptosis through an ERα-dependent mechanism. However, the contribution of ERβ in quercetin-induced apoptosis remains elusive. Here, we report that quercetin, at nutritionally relevant concentrations, mimicked the 17β-estradiol (E2)-induced apoptotic effect in both ERβ1-transfected HeLa and in ERβ1-containing DLD-1 colon cancer cell lines by inducing the activation of p38. p38 activation is responsible for pro-apoptotic activation of caspase-3 and the cleavage of poly(ADP-ribose) polymerase. Notably, no inactivation or downregulation of the survival kinases (i.e., AKT and ERK1/2) or the antiapoptotic protein Bcl-2 was observed after quercetin stimulation. On the contrary, quercetin acted similarly to E2 by increasing the levels of the oncosuppressor protein PTEN and by impeding ERβ-dependent cyclin D1 promoter activity, which subsequently resulted in the transcription of the estrogen-responsive element remaining unchanged. As a whole, these data indicate that quercetin mimics the E2 effects in the presence of ERβ1, thus maintaining its anti-carcinogenic potential. In addition, the quercetin pro-apoptotic action in the presence of ERα may render it as a dual-sided protective agent against E2-related cancer in the reduction of tumour growth in organs that express ERα and/or ERβ.


Interaction with type II estrogen binding sites and antiproliferative activity of tamoxifen and quercetin in human non-small-cell lung cancer.
            (Caltagirone et al., 1997) Download
The antiestrogen tamoxifen is thought to antagonize the effects of estrogens by competing with them for estrogen receptor (ER) binding. However, tarnoxifen can also reverse multidrug resistance, synergize with cisplatin cytotoxicity, and inhibit growth in ER-negative lung cancer cells. In addition to ERs, rat and human target tissues contain a second binding macromolecule termed the type II estrogen binding site (type II EBS). It has been shown that tamoxifen and flavonoids, a widely distributed class of natural substances with a variety of biologic actions, bind to type II EBS and inhibit the growth of several tumor cell types. At present, conflicting data about ERs and an absence of data about type II EBSs exist for lung tumors. We have tested non-small-cell lung carcinoma cell lines and primary tumor cells for the presence of ERs and type II EBSs and have evaluated the effects of tamoxifen and quercetin (pentahydroxyflavone) on the growth of these cells. Using a whole-cell assay and nuclear and cytosolic radiobinding experiments with [3H]estradiol as tracer, we have found that SK-LU1, SW900, ChaGo-K-1, H441, H661, and A549 cells, as well as primary tumors, bind estrogen specifically. This binding results mainly from the presence of a large number of type II EBSs, whereas ERs are absent or present at low concentrations. Type II EBSs bound tamoxifen and quercetin with similar affinity. Cell counts and a thymidine incorporation assay showed that both compounds inhibit cell growth in a concentration-dependent manner at concentrations ranging from 10 nM to 1 microM. Neither ipriflavone, an isoflavone, nor rutin, the 3-rhamnosylglucoside of quercetin, bound type II EBSs or inhibited cell growth. These findings suggest that tamoxifen and quercetin could regulate lung cancer cell growth through a binding interaction with type II EBSs. This mechanism could also be active in vivo, in that we have observed that nuclear and cytosolic type II EBSs were present in all primary lung cancers tested (n = 12), and that tamoxifen and quercetin were effective in inhibiting in vitro bromodeoxyuridine (BrdU) incorporation and proliferation-cell nuclear antigen expression by neoplastic cells in these cancers.


Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis.
            (Cruz-Correa et al., 2006) Download
BACKGROUND & AIMS:  Familialadenomatous polyposis (FAP) is an autosomal-dominant disorder characterized by the development of hundreds of colorectal adenomas and eventual colorectal cancer. Regression of adenomas in this syndrome occurs with the administration of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors, but these compounds can have considerable side effects. We evaluated the efficacy of the combination of diet-derived nonprescription supplements curcumin and quercetin to regress adenomas in patients with FAP. METHODS:  Five FAP patients with prior colectomy (4 with retained rectum and 1 with an ileal anal pouch) received curcumin 480 mg and quercetin 20 mg orally 3 times a day. The number and size of polyps were assessed at baseline and after therapy. The Wilcoxon signed-rank test was used to determine differences in the number and size of polyps. Treatment side effects and medication compliance also were evaluated. RESULTS:  All 5 patients had a decreased polyp number and size from baseline after a mean of 6 months of treatment with curcumin and quercetin. The mean percent decrease in the number and size of polyps from baseline was 60.4% (P < .05) and 50.9% (P < .05), respectively. Minimal adverse side effects and no laboratory abnormalities were noted. CONCLUSIONS:  The combination of curcumin and quercetin appears to reduce the number and size of ileal and rectal adenomas in patients with FAP without appreciable toxicity. Randomized controlled trials are needed to validate these findings.

Life or death: neuroprotective and anticancer effects of quercetin.
            (Dajas, 2012) Download
ETHNOPHARMACOLOGICAL RELEVANCE:  Quercetin is a ubiquitous flavonoid that is present in numerous plants that are utilized in many different cultures for their nervous system and anticancer effects. To better understand the neuroprotective and antiproliferative activities of quercetin, we present a comprehensive review of the divergent actions that contribute to the ethnopharmacological profile of these plants. RESULTS:  The pharmacological activities of quercetin that modulate antioxidation/oxidation/kinase-signaling pathways might be differentially elicited in neurons compared with malignant cells, ultimately promoting cell survival or death in a cell type- and metabolism-specific manner. Whereas the broad antioxidation and anti-inflammatory activities of quercetin are important for neuronal survival, the oxidative, kinase- and cell cycle-inhibitory, apoptosis-inducing effects of quercetin are essential for its anticancer effects. The diverse mechanistic interactions and activities of quercetin that modulate the phosphorylation state of molecules as well as gene expression would alter the interconnected and concerted intracellular signaling equilibrium, either inhibiting or strengthening survival signals. These mechanisms, which have been mainly observed in in vitro studies, cannot be easily translated into an explanation of the divergent simultaneous neuroprotective and anticancer effects observed in vivo. This is in part due to low bioavailability in plasma and in the brain, as well as the nature of the actual active molecules. CONCLUSIONS:  Numerous studies have demonstrated the beneficial effects of chronic quercetin intake, which is ethnopharmacologically meaningful, as many plants that are chronically ingested by people contain quercetin. Although quercetin and quercetin-containing plants exhibit potential as therapeutic modalities in neuropathology and in cancer, the data collectively highlight the need to elucidate issues such as bioavailability as well as its correlation with effectiveness at biomarkers in vivo. There would be an increased potentential of these plants for chemoprevention and neuropathology prevention.

Quercetin prevents experimental glucocorticoid-induced osteoporosis: a comparative study with alendronate.
            (Derakhshanian et al., 2013) Download
Glucocorticoid-induced osteoporosis (GIO) is the most common type of secondary osteoporosis. The aim of this study was to compare the efficacy of quercetin, a plant-derived flavonoid, with alendronate in the prevention of GIO. Fifty-six Sprague-Dawley rats were randomly distributed among 7 groups (8 rats per group) and treated for 6 weeks with one of the following: (i) normal saline; (ii) 40 mg methylprednisolone sodium succinate (MP)/kg body mass; (iii) MP + 40 μg alendronate/kg; (iv) MP + 50 mg quercetin/kg; (v) MP + 40 μg alendronate/kg + 50 mg quercetin/kg; (vi) MP + 150 mg quercetin/kg; and (vii) MP + 40 μg alendronate/kg + 150 mg quercetin/kg. MP and alendronate were injected subcutaneously and quercetin was administered by oral gavage 3 days a week. At the end of the study, femur breaking strength was significantly decreased as a consequence of MP injection. This decrease was completely compensated for in groups receiving 50 mg quercetin/kg plus alendronate, and 150 mg quercetin/kg with or without alendronate. Quercetin noticeably elevated osteocalcin as a bone formation marker, while alendronate did not show such an effect. In addition, administration of 150 mg quercetin/kg increased femoral trabecular and cortical thickness by 36% and 22%, respectively, compared with the MP-treated group. These data suggest that 150 mg quercetin/kg, alone or in combination with alendronate, can completely prevent GIO through its bone formation stimulatory effect.

Therapeutic properties of quercetin on monosodium urate crystal-induced inflammation in rat.
            (Huang et al., 2012) Download
OBJECTIVES:  Gouty arthritis is characterized by intense, acute inflammatory reactions that occur in response to articular deposits of monosodium urate crystals. In this study we have assessed the effects of the flavonoid, quercetin, on monosodium urate crystal-induced inflammation in rats, an experimental model for gouty arthritis. METHODS:  Gouty arthritis was induced by intra-articular injection of monosodium urate crystal suspension inside the ankle joint of the rat right hind limb. Circumference was assessed at 2, 4, 8, 12, 24, and 48 h after monosodium urate crystal injection. Histopathological analysis of joint synovial tissue, inflammatory mediator levels, lipid peroxidation, and antioxidant status in serum, liver and joint synovial tissue were determined in control and monosodium urate crystal-treated rats at the end of experiment. KEY FINDINGS:  Quercetin treatment attenuated oedema in a dose-dependent manner and decreased histological signs of acute inflammation in the treated animals. In addition, quercetin treatment suppressed leucocyte recruitment, decreased chemokine levels, decreased levels of the lipid peroxidation end-product malondialdehyde, and increased antioxidant enzyme activity in treated rats. CONCLUSIONS:  These results indicated that quercetin exerted a strong anti-inflammatory effect that may be useful for the treatment of acute gouty arthritis.

Quercetin supplementation: insight into the potentially harmful outcomes of neurodegenerative prevention.
            (Jazvinšćak Jembrek et al., 2012) Download
Dietary antioxidant supplements have been considered for the prevention of neuronal oxidative injury and death. Recent studies indicate that excessive antioxidants could exert adverse effects, thereby questioning the safety of prolonged supplementation. The aim of our study was to investigate the effects of quercetin (up to 150 μM), the ubiquitous plant-derived flavonoid and highly potent scavenger of reactive oxygen species (ROS) on healthy P19 neurons, in order to assess the efficacy and safety of its long-term use in neurodegenerative prevention. Although exposure for 24 h to quercetin did not compromise neuronal survival, morphological examination revealed diminished neuronal branching, a finding probably related to an observed decrease in lactate dehydrogenase activity. Using 2',7'-dichlorofluorescin diacetate and dot-blot analysis, we found reduced basal levels of ROS and 4-hydroxy-2-nonenal, a biomarker of lipid peroxidation, confirming the antioxidative mechanism of quercetin action. Unexpectedly, quercetin also depleted intracellular glutathione content. Reverse transcriptase PCR and western blot analysis showed depletion of total RNA amount and changes in the expression of cell survival regulating genes Bcl-2, p53, and c-fos. Nuclear condensation and caspase-3/7 activity, phenomena related to programmed cell death cascade, were not affected. The potential risk of observed changes indicates that quercetin-enriched supplements should be taken with caution. The diversity of quercetin effects and complexity of possible intracellular interactions between affected genes pointed out the necessity for additional pharmacological and toxicological studies in order to better elucidate the mechanisms of quercetin action and to recognize its potential side effects at higher doses and during long-term administration.


Chronic dietary intake of quercetin alleviates hepatic fat accumulation associated with consumption of a Western-style diet in C57/BL6J mice.
            (Kobori et al., 2011) Download
SCOPE:  To determine the effect of consumption of a quercetin-rich diet on obesity and dysregulated hepatic gene expression. METHODS AND RESULTS:  C56BL/6J mice were fed for 20 wk on AIN93G (control) or a Western diet high in fat, cholesterol and sucrose, both with or without 0.05% quercetin. Triglyceride levels in plasma, thiobarbituric acid-reactive substances (oxidative stress marker) and glutathione levels and peroxisome proliferator-activated receptor α expression in livers of mice fed with the Western diet were all improved after 8 wk feeding with quercetin. After 20 wk, further reductions of visceral and liver fat accumulation and improved hyperglycemia, hyperinsulinemia, dyslipidemia and plasma adiponectin and TNFα levels in these mice fed with quercetin were observed. The expression of hepatic genes related to steatosis, such as peroxisome proliferator-activated receptor γ and sterol regulatory element-binding protein-1c was also normalized by quercetin. In mice fed with the control diet, quercetin did not affect body weight but reduces the plasma TNFα and hepatic thiobarbituric acid-reactive substance levels. CONCLUSION:  In mice fed with a Western diet, chronic dietary intake of quercetin reduces liver fat accumulation and improves systemic parameters related to metabolic syndrome, probably mainly through decreasing oxidative stress and reducing PPARα expression, and the subsequent reduced expression in the liver of genes related to steatosis.

Oral administration of quercetin inhibits bone loss in rat model of diabetic osteopenia.
            (Liang et al., 2011) Download
Diabetic osteopenia can result in an increased incidence of bone fracture and a delay in fracture healing. Quercetin, one of the most widely distributed flavonoids in plants, possesses antioxidant property and beneficial effect on osteoporosis in ovariectomized mice. All these properties make quercetin a potential candidate for controlling the development of diabetic osteopenia. Therefore, the present study was designed to investigate the putative beneficial effect of quercetin on diabetic osteopenia in rats. Diabetes mellitus was induced by streptozotocin. The diabetic rats received daily oral administration of quercetin (5mg/kg, 30 mg/kg and 50mg/kg) for 8 weeks, which was started at 4 weeks after streptozotocin injection. Quercetin at 5mg/kg showed little effect on diabetic osteopenia, while quercetin at 30 mg/kg and 50mg/kg could increase the decreased serum osteocalcin, serum alkaline phosphatase activity, and urinary deoxypyridinoline in diabetic rats. In addition, quercetin (30 mg/kg and 50mg/kg) could partially reverse the decreased biomechanical quality and the impaired micro-architecture of the femurs in diabetic rats. Histomorphometric analysis showed that both decreased bone formation and resorption were observed in diabetic rats, which was partially restored by quercetin (30 mg/kg and 50mg/kg). Further investigations showed that quercetin significantly lowered the oxidative DNA damage level, up-regulated the total serum antioxidant capability and the activity of serum antioxidants in diabetic rats. All those findings indicate the beneficial effect of quercetin on diabetic osteopenia in rats, and raise the possibility of developing quercetin as potential drugs or an ingredient in diet for controlling diabetic osteopenia.

Reduction of rat prostate weight by combined quercetin-finasteride treatment is associated with cell cycle deregulation.
            (Ma et al., 2004) Download
Benign prostate hyperplasia and prostate cancer are major public health problems. We report herein that daily treatment of male rats with 50, 100 or 150 mg quercetin per kg body weight resulted in serum concentrations of quercetin equivalent to 25.3 microM, 43.3 microM and 54.3 microM respectively. Concomitantly, serum testosterone levels were increased by 1.79-, 1.83- and 3.48-fold, while serum dihydrotestosterone (DHT) levels were 125%, 92% and 73% of the control. A slight increase in prostate weight coupled with dilated prostate lumens full of secretory materials were observed. Finasteride alone caused a significant decrease in serum DHT level and prostate weight. Co-administration of quercetin with finasteride prevented the finasteride-induced decrease in serum DHT levels but significantly enhanced the reduction in wet prostate weight, which was reduced by 26.9% in finasteride-treated animals to 31.8%, 40.0% and 48.2% after finasteride given together with the three doses of quercetin. The combined treatment altered cell cycle-regulated proteins in a wide spectrum. The expressions of cyclin D1, CDK-4, cdc-2 and phospho-cdc-2 at tyrosine 15, phospho-MEK1/2, phospho-MAP kinase, phospho-pRb at serine 780 and serine 807/811 were significantly inhibited, while the levels of p15, p21 and p27 were increased. In conclusion, quercetin-finasteride treatments caused wide cell cycle deregulation in rat prostates, which, in turn, decreased the proliferation rate, changed the secretion activities of epithelial cells and resulted in a marked reduction in wet prostate weight. The results suggest that quercetin synergizes with finasteride to reduce the wet prostate weight through a cell cycle-related pathway, which may be androgen independent.

Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats.
            (Panchal et al., 2012) Download
Metabolic syndrome is a risk factor for cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). We investigated the responses to the flavonol, quercetin, in male Wistar rats (8-9 wk old) divided into 4 groups. Two groups were given either a corn starch-rich (C) or high-carbohydrate, high-fat (H) diet for 16 wk; the remaining 2 groups were given either a C or H diet for 8 wk followed by supplementation with 0.8 g/kg quercetin in the food for the following 8 wk (CQ and HQ, respectively). The H diet contained ~68% carbohydrates, mainly as fructose and sucrose, and ~24% fat from beef tallow; the C diet contained ~68% carbohydrates as polysaccharides and ~0.7% fat. Compared with the C rats, the H rats had greater body weight and abdominal obesity, dyslipidemia, higher systolic blood pressure, impaired glucose tolerance, cardiovascular remodeling, and NAFLD. The H rats had lower protein expressions of nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), and carnitine palmitoyltransferase 1 (CPT1) with greater expression of NF-kappaB in both the heart and the liver and less expression of caspase-3 in the liver than in C rats. HQ rats had higher expression of Nrf2, HO-1, and CPT1 and lower expression of NF-kappaB than H rats in both the heart and the liver. HQ rats had less abdominal fat and lower systolic blood pressure along with attenuation of changes in structure and function of the heart and the liver compared with H rats, although body weight and dyslipidemia did not differ between the H and HQ rats. Thus, quercetin treatment attenuated most of the symptoms of metabolic syndrome, including abdominal obesity, cardiovascular remodeling, and NAFLD, with the most likely mechanisms being decreases in oxidative stress and inflammation.

Site-specific anticancer effects of dietary flavonoid quercetin.
            (Sak, 2014) Download
Food-derived flavonoid quercetin, widely distributed in onions, apples, and tea, is able to inhibit growth of various cancer cells indicating that this compound can be considered as a good candidate for anticancer therapy. Although the exact mechanism of this action is not thoroughly understood, behaving as antioxidant and/or prooxidant as well as modulating different intracellular signalling cascades may all play a certain role. Such inhibitory activity of quercetin has been shown to depend first of all on cell lines and cancer types; however, no comprehensive site-specific analysis of this effect has been published. In this review article, cytotoxicity constants of quercetin measured in various human malignant cell lines of different origin were compiled from literature and a clear cancer selective action was demonstrated. The most sensitive malignant sites for quercetin revealed to be cancers of blood, brain, lung, uterine, and salivary gland as well as melanoma whereas cytotoxic activity was higher in more aggressive cells compared to the slowly growing cells showing that the most harmful cells for the organism are probably targeted. More research is needed to overcome the issues of poor water solubility and relatively low bioavailability of quercetin as the major obstacles limiting its clinical use.

Quercitrin and taxifolin stimulate osteoblast differentiation in MC3T3-E1 cells and inhibit osteoclastogenesis in RAW 264.7 cells.
            (Satué et al., 2013) Download
Flavonoids are natural antioxidants that positively influence bone metabolism. The present study screened among different flavonoids to identify biomolecules for potential use in bone regeneration. For this purpose, we used MC3T3-E1 and RAW264.7 cells to evaluate their effect on cell viability and cell differentiation. First, different doses of chrysin, diosmetin, galangin, quercitrin and taxifolin were analyzed to determine the optimum concentration to induce osteoblast differentiation. After 48h of treatment, doses ≥100μM of diosmetin and galangin and also 500μM taxifolin revealed a toxic effect on cells. The same effect was observed in cells treated with doses ≥100μM of chrysin after 14 days of treatment. However, the safe doses of quercitrin (200 and 500μM) and taxifolin (100 and 200μM) induced bone sialoprotein and osteocalcin mRNA expression. Also higher osteocalcin secreted levels were determined in 100μM taxifolin osteoblast treated samples when compared with the control ones. On the other hand, quercitrin and taxifolin decreased Rankl gene expression in osteoblasts, suggesting an inhibition of osteoclast formation. Indeed, osteoclastogenesis suppression by quercitrin and taxifolin treatment was observed in RAW264.7 cells. Based on these findings, the present study demonstrates that quercitrin and taxifolin promote osteoblast differentiation in MC3T3-E1 cells and also inhibit osteoclastogenesis in RAW264.7 cells, showing a positive effect of these flavonoids on bone metabolism.

Quercetin, kaempferol and biapigenin from Hypericum perforatum are neuroprotective against excitotoxic insults.
            (Silva et al., 2008) Download
In the present study we investigated the effects of phenolic compounds present in Hypericum perforatum against neuronal excitotoxicity and mitochondrial dysfunction. Quercetin, kaempferol and biapigenin significantly reduced neuronal death caused by 100 microM kainate plus 100 microM N-methyl-D-aspartate. The observed neuroprotection was correlated with prevention of delayed calcium deregulation and with the maintenance of mitochondrial transmembrane electric potential. The three compounds were able to reduce mitochondrial lipid peroxidation and loss of mitochondrial transmembrane electric potential caused by oxidative stress induced by ADP plus iron. Moreover, biapigenin was also able to significantly affect mitochondrial bioenergetics and decrease the capacity of mitochondria to accumulate calcium. Taken together, the results suggest that the neuroprotective action induced by quercetin and kaempferol are mainly mediated by antioxidant effects, whereas biapigenin mainly affects mitochondrial bioenergetics and calcium uptake.

Dietary quercetin inhibits bone loss without effect on the uterus in ovariectomized mice.
            (Tsuji et al., 2009) Download
Quercetin is a major dietary flavonoid found in onions and other vegetables, and potentially has beneficial effects on disease prevention. In the present study, we demonstrate for the first time the effects of dietary quercetin on bone loss and uterine weight loss by ovariectomy in vivo. Female mice were ovariectomized (OVX) and were randomly allocated to 3 groups: a control diet or a diet with 0.25% (LQ) or 2.5% quercetin (HQ). After 4 weeks, dietary quercetin had no effects on uterine weight in OVX mice, but bone mineral density of the lumbar spine L4 and femur measured by peripheral quantitative computed tomography (pQCT) was higher in both the sham and the HQ groups than in the OVX group. Histomorphometric analysis showed that the HQ group restored bone volume (BV/TV) completely in distal femoral cancellous bone, but did not reduce the osteoclast surface area and osteoclast number when compared with the OVX group. In in-vitro experiments using mouse monocyte/macrophage cell line RAW264.7 cells, however, quercetin and its conjugate, quercetin-3-O-beta-D: -glucuronide dose-dependently inhibited the receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast differentiation, and the RANKL-stimulated expression of osteoclast related genes was also inhibited by quercetin. The luciferase reporter assay showed that quercetin did not appear to have estrogenic activity through estrogen receptors. These results suggest that dietary quercetin inhibits bone loss without effect on the uterus in OVX mice and does not act as a potent inhibitor of osteoclastogenesis or as a selective estrogen receptor modulator in vivo.

Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells.
            (Wenzel et al., 2004) Download
A high dietary intake of plant foods is thought to contribute to the prevention of colorectal cancers in humans and flavonoids as part of such a diet are considered to contribute to those protective effects. Quercetin is a major dietary flavonoid consumed with a diet rich in onions, tea, and apples. We used HT-29 human colon cancer cells and investigated the effects of quercetin on proliferation, apoptosis, and differentiation as processes shown to be disregulated during cancer development. To identify the cellular targets of quercetin action, two-dimensional gel electrophoresis was performed and proteins altered in expression level after quercetin exposure of cells were identified by mass spectrometry of peptide fragments generated by tryptic digestion. Quercetin inhibited the proliferation of HT-29 cells with an IC(50)-value of 81.2 +/- 6.6 microM. Cell differentiation based on surface expression of alkaline phosphatase was enhanced 4-fold and the activity of the pro-apoptotic effector caspase-3 increased 3-fold. Those effects were associated with the regulation of heat-shock proteins and annexins shown to both play a crucial role in the process of apoptosis. Cytoskeletal caspase substrates were found as regulated as well and various proteins involved in intermediary metabolism and in gene regulation showed altered steady-state expression levels upon quercetin treatment of cells. In conclusion, quercetin alters the levels of a variety of proteins involved in growth, differentiation, and apoptosis of colon cancer cells. Their identification as molecular targets of quercetin may explain the anti-cancer activities of this flavonoid.


Protective effects of onion-derived quercetin on glutamate-mediated hippocampal neuronal cell death.
            (Yang et al., 2013) Download
BACKGROUND:  Neurodegenerative diseases are characterized by progressive neuron degeneration in specific functional systems of the central or peripheral nervous system. This study investigated the protective effects of quercetin isolated from onion on neuronal cells and its protective mechanisms against glutamate-induced apoptosis in HT22 cells. MATERIALS AND METHODS:  HT22 cells were cultured to study the neuroprotective mechanism of quercetin against glutamate-mediated oxidative stress. The intracellular reactive oxygen species (ROS) level and mitochondrial membrane potential (ΔΨm) were measured. The protein expression of calpain, spectrin, Bcl-2, Bax, Bid, cytochrome c, and mitogen-activated protein kinases (MAPKs) was evaluated by Western blotting. RESULTS:  Quercetin had a protective effect by reducing both intracellular ROS overproduction and glutamate-mediated Ca(2+) influx. These effects were due to the downregulation of several apoptosis-related biochemical markers. Calpain expression was reduced and spectrin cleavage was inhibited by quercetin in glutamate-exposed HT22 cells. Disruption of the mitochondrial membrane potential (ΔΨm), activation of the pro-apoptotic proteins Bid and Bax, and cytochrome c release in response to glutamate-induced oxidative stress were reduced. Quercetin also suppressed phosphorylation of MAPKs. CONCLUSION:  This is the first report on the detailed mechanisms of the protective effect of quercetin on HT22 cells. Onion extract and quercetin may be useful for preventing or treating neurodegenerative disorders.

Does Quercetin Improve Cardiovascular Risk factors and Inflammatory Biomarkers in Women with Type 2 Diabetes: A Double-blind Randomized Controlled Clinical Trial.
            (Zahedi et al., 2013) Download
BACKGROUND:  Quercetin has been distributed in a wide range of foods, but some of its known effects in vitro, are not proven in human studies. Therefore, the aim of this study was evaluation of the effects of quercetin intake on cardiovascular risk factors and inflammatory biomarkers in women with type 2 diabetes. METHODS:  This double-blind randomized clinical trial was carried out on 72 women for 10 weeks. Subjects were assigned to quercetin and placebo groups using a permutated block randomization of size two. Quercetin was given to participants as a 500 mg capsule daily. Biochemical variables were measured at baseline and at the end of the study, and changes were compared using appropriate statistical methods. RESULTS:  Compared with placebo, quercetin intake decreased systolic blood pressure significantly (-8.8 ± 9.3 vs. -3.5 ± 11.7, P = 0.04). Although changes in diastolic blood pressure between the groups was not significant (P = 0.19), high-density lipoprotein cholesterol (HDL-C) was significantly decreased in both groups while changes in total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and ratio of TG/HDL-C and LDL-C/HDL-C were not significant between and within groups. Quercetin supplementation significantly reduced the serum concentration of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) (P = 0.01 and P < 0.0001, respectively); however, the mean changes in serum levels of IL-6, TNF-α, and high-sensitivity C-reactive protein were not significant between the groups. CONCLUSIONS:  Quercetin supplementation reduced systolic blood pressure significantly but had no effect on other cardiovascular risk factors and inflammatory biomarkers. Considering the biological effects of quercetin in vitro, we need more studies with a stronger design and sample size with different doses of quercetin.



Arias, N, et al. (2014), ‘Quercetin can reduce insulin resistance without decreasing adipose tissue and skeletal muscle fat accumulation.’, Genes Nutr, 9 (1), 361. PubMed: 24338341
Arredondo, F, et al. (2010), ‘After cellular internalization, quercetin causes Nrf2 nuclear translocation, increases glutathione levels, and prevents neuronal death against an oxidative insult.’, Free Radic Biol Med, 49 (5), 738-47. PubMed: 20554019
Bulzomi, P, et al. (2012), ‘The pro-apoptotic effect of quercetin in cancer cell lines requires ERβ-dependent signals.’, J Cell Physiol, 227 (5), 1891-98. PubMed: 21732360
Caltagirone, S, et al. (1997), ‘Interaction with type II estrogen binding sites and antiproliferative activity of tamoxifen and quercetin in human non-small-cell lung cancer.’, Am J Respir Cell Mol Biol, 17 (1), 51-59. PubMed: 9224209
Cruz-Correa, M, et al. (2006), ‘Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis.’, Clin Gastroenterol Hepatol, 4 (8), 1035-38. PubMed: 16757216
Dajas, F (2012), ‘Life or death: neuroprotective and anticancer effects of quercetin.’, J Ethnopharmacol, 143 (2), 383-96. PubMed: 22820241
Derakhshanian, H, et al. (2013), ‘Quercetin prevents experimental glucocorticoid-induced osteoporosis: a comparative study with alendronate.’, Can J Physiol Pharmacol, 91 (5), 380-85. PubMed: 23656499
Huang, J, et al. (2012), ‘Therapeutic properties of quercetin on monosodium urate crystal-induced inflammation in rat.’, J Pharm Pharmacol, 64 (8), 1119-27. PubMed: 22775215
Jazvinšćak Jembrek, M, et al. (2012), ‘Quercetin supplementation: insight into the potentially harmful outcomes of neurodegenerative prevention.’, Naunyn Schmiedebergs Arch Pharmacol, 385 (12), 1185-97. PubMed: 23073654
Kobori, M, et al. (2011), ‘Chronic dietary intake of quercetin alleviates hepatic fat accumulation associated with consumption of a Western-style diet in C57/BL6J mice.’, Mol Nutr Food Res, 55 (4), 530-40. PubMed: 21462320
Liang, W, et al. (2011), ‘Oral administration of quercetin inhibits bone loss in rat model of diabetic osteopenia.’, Eur J Pharmacol, 670 (1), 317-24. PubMed: 21914440
Ma, Z, et al. (2004), ‘Reduction of rat prostate weight by combined quercetin-finasteride treatment is associated with cell cycle deregulation.’, J Endocrinol, 181 (3), 493-507. PubMed: 15171697
Panchal, SK, H Poudyal, and L Brown (2012), ‘Quercetin ameliorates cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats.’, J Nutr, 142 (6), 1026-32. PubMed: 22535755
Sak, K (2014), ‘Site-specific anticancer effects of dietary flavonoid quercetin.’, Nutr Cancer, 66 (2), 177-93. PubMed: 24377461
Satué, M, et al. (2013), ‘Quercitrin and taxifolin stimulate osteoblast differentiation in MC3T3-E1 cells and inhibit osteoclastogenesis in RAW 264.7 cells.’, Biochem Pharmacol, 86 (10), 1476-86. PubMed: 24060614
Silva, B, et al. (2008), ‘Quercetin, kaempferol and biapigenin from Hypericum perforatum are neuroprotective against excitotoxic insults.’, Neurotox Res, 13 (3-4), 265-79. PubMed: 18522906
Tsuji, M, et al. (2009), ‘Dietary quercetin inhibits bone loss without effect on the uterus in ovariectomized mice.’, J Bone Miner Metab, 27 (6), 673-81. PubMed: 19495926
Wenzel, U, et al. (2004), ‘Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells.’, Proteomics, 4 (7), 2160-74. PubMed: 15221776
Yang, EJ, et al. (2013), ‘Protective effects of onion-derived quercetin on glutamate-mediated hippocampal neuronal cell death.’, Pharmacogn Mag, 9 (36), 302-8. PubMed: 24124281
Zahedi, M, et al. (2013), ‘Does Quercetin Improve Cardiovascular Risk factors and Inflammatory Biomarkers in Women with Type 2 Diabetes: A Double-blind Randomized Controlled Clinical Trial.’, Int J Prev Med, 4 (7), 777-85. PubMed: 24049596