槲皮素体外抗肺癌作用研究进展

槲皮素是一个含有邻二酚羟基和间二酚羟基的黄酮醇类化合物。为了探析槲皮素体外抗肺癌现状,本文通过国内知网、万方,输入“槲皮素”、“肺癌”、“槲皮素衍生物”等,国外SpringerLink、PubMed数据库查阅了“lung cancer”、“ quercetin”、“quercetin derivative”等主题词,检索了近年槲皮素及其衍生物在抗肺癌方面研究的相关数据,综述了其新制剂、衍生物和作用机制。槲皮素抗肺癌新制剂有纳米粒、纳米乳、纳米胶束、脂质体和其他制剂。从已合成的120余个槲皮素衍生物中发现了11个对肺癌作用强于槲皮素的化学成分。通过诱导细胞凋亡、抑制酶的活性、阻滞细胞周期、逆转肿瘤耐药性等作用发挥抗肺癌作用,以期为槲皮素及其衍生物在肺癌方面研究开发利用提供依据。     

Effect of flavonoids on learning,memory and neurocognitive performance: relevance and potential implications for Alzheimer's disease pathophysiology

Recent evidence has indicated that a group of plant‐derived compounds known as flavonoids may exert particularly powerful actions on mammalian cognition and may reverse age‐related declines in memory and learning. In addition, growing evidence is also suggestive that flavonoids may delay the development of Alzheimer's disease‐like pathology, suggestive of potential dietary strategies in dementia. Although these low‐molecular‐weight phytochemicals are absorbed to only a limited degree, they have been found to counteract age‐related cognitive declines possibly via their ability to interact with the cellular and molecular architecture of the brain responsible for memory. However, the majority of the research has been carried out at rather supraphysiological concentrations and only a few studies have investigated the neuromodulatory effects of physiologically attainable flavonoid concentrations. This review will summarize the evidence for the effects of flavonoids and their metabolites in age‐related cognitive decline and Alzheimer's disease. Mechanisms of actions will be discussed and include those activating signalling pathways critical in controlling synaptic plasticity, reducing neuroinflammation and inducing vascular effects potentially capable of causing new nerve cell growth in the hippocampus. Altogether, these processes are known to be important in maintaining optimal neuronal function, to limit neurodegeneration and to prevent or reverse age‐dependent deteriorations in cognitive performance. © 2013 Society of Chemical Industry     

Effect of quercetin on learning and memory performance in ICR mice under neurotoxic trimethyltin exposure

To investigate the anti-amnesic effect of quercetin by using in vivo Y-maze and passive avoidance tests, the learning and memory impairment in ICR mice was induced by neurotoxic trimethyltin. Quercetin pre-administration attenuated TMT-induced memory injury in both in vivo tests. Acetylcholinesterase (AChE), prepared from mice brain tissues, was inhibited by quercetin in a dose-dependent manner. Malondialdehyde generation in the brain homogenate of mice treated with quercetin decreased, indicating that peroxidation of polyunsaturated fatty acids was inhibited by the cellular membrane. In addition, potent antioxidant capacity of quercetin was confirmed through various antioxidative assays. Our findings suggest that the quercetin may improve cognitive ability against TMT-induced neuronal deficit and also have an inhibitory action against AChE. Consequently, these results demonstrate that the quercetin could possess a wide range of beneficial activities for neurodegenerative disorders, notably Alzheimer’s disease (AD).     

Comparison of fisetin and quercetin oxidation with a cell‐free extract of onion trimmings and peel,plant waste,containing peroxidase enzyme: a further insight into flavonol degradation mechanism

A peroxidase‐active, cell‐free extract prepared from onion solid wastes was studied with regard to its biocatalytic properties, using fisetin (3,3′,4′,7‐tetrahydroxyflavone) as substrate. This particular substrate was selected to investigate specifically the role of the A‐ring of the flavonol skeleton in the oxidisability and cleavage pathway(s), and ascertain whether changes in substitution pattern may affect product formation, compared with quercetin (3,3′,4′,5,7‐pentahydroxyflavone). Oxidation was shown to be optimum at pH values between 5 and 7 and temperatures between 20 and 40 °C. HPLC analyses of a fisetin solution treated with the cell‐free extract revealed the formation of three major products, including 3,4‐dihydroxybenzoic acid (protocatechuic acid), 2,4‐dihydroxybenzoic acid (β‐resorcylic acid) and the depside 2‐(3,4‐dihydroxybenzyloxy)‐4‐dihydroxybenzoic acid. The tentative identification of these substances permitted an approach to a putative oxidation pathway, which appeared to have important similarities with that of quercetin.     

Vascular deconjugation of quercetin glucuronide: The flavonoid paradox revealed?

Scope: The dietary flavonoid quercetin exerts protective cardiovascular effects. Because quercetin is rapidly metabolized into less active or inactive glucuronidated metabolites and the plasma concentrations of free quercetin are very low, a huge amount of scientific data generated along decades with the unconjugated compounds in vitro has been questioned. We aimed to determine whether glucuronidated quercetin can deconjugate in situ and whether deconjugation leads to a biological effect. Methods and results: Quercetin and quercetin‐3‐O‐glucuronide (Q3GA) were perfused through the isolated rat mesenteric vascular bed. Quercetin was rapidly metabolized in the mesentery. In contrast, the decay of Q3GA was slower and was accompanied by a progressive increase of quercetin in the perfusate and in the tissue over 6 h, which was prevented by the β‐glucuronidase inhibitor saccharolactone. Incubation of mesenteric arterial rings mounted in a wire myograph with Q3GA for ≥1 h resulted in a significant inhibition of the contractile response which was also prevented by saccharolactone. Moreover, the intravenous administration of Q3GA resulted in a slow onset and sustained blood pressure lowering effect, demonstrating for the first time that Q3GA has effects in vivo. Conclusion: We propose that Q3GA behaves as a quercetin carrier in plasma, which deconjugates in situ releasing the aglycone which is the final effector.     

Cover Caption

September Online Cover : Possible molecular mechanisms of quercetin in improvement of memory impairment., from “Quercetin in Food: Possible Mechanisms of Its Effect on Memory”, by Fatemeh Babaei, Mohammadreza Mirzababaei, and Marjan Nassiri‐Asl. p.2280.     

Plant flavonol quercetin and isoflavone biochanin A differentially induce protection against oxidative stress and inflammation in ARPE-19 cells

In this work, differential ability of plant flavonol quercetin and plant isoflavone biochanin A to modulate oxidative stress and inhibit inflammation-related responses was investigated using human retinal pigment epithelial cells (RPE) at gene expression level. Quercetin protected cells from oxidative stress-induced cell death, whereas biochanin A had no statistically significant protective effects. Quercetin reduced the expression of cytokines IL-6 and IL-1?? in cells treated with H₂O₂, and expression levels of Nrf2 and HO-1 were increased by quercetin treatment suggesting protective function against oxidative stress. Our data indicate that quercetin may protect cells by inhibiting the production of pro-inflammatory factors such as IL-6, and by inducing the expression of ROS-catalyzing phase II proteins such as HO-1. Therefore, plant extracts rich in flavonol quercetin may be an interesting resource for functional food products and other foods targeted for reduced risks of age-related macular degeneration.     

Dietary quercetin alleviates diabetic symptoms and reduces streptozotocin‐induced disturbance of hepatic gene expression in mice

Quercetin is a food component that may ameliorate the diabetic symptoms. We examined hepatic gene expression of BALB/c mice with streptozotocin (STZ)‐induced diabetes to elucidate the mechanism of the protective effect of dietary quercetin on diabetes‐associated liver injury. We fed normal and STZ‐induced diabetic mice with diets containing quercetin for 2 wk and compared the patterns of hepatic gene expression in these groups of mice using a DNA microarray. Diets containing 0.1 or 0.5% quercetin lowered the STZ‐induced increase in blood glucose levels and improved plasma insulin levels. A cluster analysis of the hepatic gene expressions showed that 0.5% quercetin diet suppressed STZ‐induced alteration of gene expression. Gene set enrichment analysis (GSEA) and quantitative RT‐PCR analysis showed that the quercetin diets had greatest suppressive effect on the STZ‐induced elevation of expression of cyclin‐dependent kinase inhibitor p21(WAF1/Cip1) (Cdkn1a). Quercetin also suppressed STZ‐induced expression of Cdkn1a in the pancreas. Dietary quercetin might improve liver and pancreas functions by enabling the recovery of cell proliferation through the inhibition of Cdkn1a expression. Unexpectedly, in healthy control mice the 0.5 and 1% quercetin diets reduced the expression of ubiquitin C (Ubc), which has heat‐shock element (HSE) in the promoter region, in the liver.     

Human Intestinal Dendritic Cells in Inflammatory Bowel Diseases

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a serious, costly, and persistent health problem with an estimated prevalence in Western countries around 0.5% of the general population; its socioeconomic impact is comparable with that for chronic diseases such as diabetes. Conventional treatment involves escalating drug regimens with concomitant side effects followed, in some cases, by surgical interventions, which are often multiple, mainly in Crohn's disease. The goal of finding a targeted gut‐specific immunotherapy for IBD patients is therefore an important unmet need. However, to achieve this goal we first must understand how dendritic cells (DC), the most potent antigen present cells of the immune system, control the immune tolerance in the gastrointestinal tract and how their properties are altered in those patients suffering from IBD. In this review, we summarize the current available information regarding human intestinal DC subsets composition, phenotype, and function in the human gastrointestinal tract describing how, in the IBD mucosa, DC display pro‐inflammatory properties, which drive disease progression. A better understanding of the mechanisms inducing DC abnormal profile in IBD may provide us with novel tools to perform tissue specific immunomodulation.     

Characterisation of anti‐Staphylococcus aureus activity of quercetin

Although many antibiotics are available for the treatment of bacterial infections, the emergence and global spread of antibiotic‐resistant bacteria is a community‐wide problem. To overcome this problem, we must explore alternative antimicrobials. This study investigated the antibacterial properties of quercetin, a flavonoid present in vegetables and fruits. Quercetin was tested against gram‐positive and gram‐negative bacteria and was found to exert selective antibacterial activity against Staphylococcus aureus, including methicillin‐resistant S. aureus (MRSA), and Staphylococcus epidermidis. Some clinical MRSA strains showed remarkable susceptibility to quercetin. In combination with antibiotics, such as oxacillin, ampicillin, vancomycin, gentamicin, and erythromycin, quercetin showed markedly enhanced antibacterial activity against MRSA. We also report quercetin‐induced aggregation of S. aureus cells; the morphological changes in these cells, as assessed by electron microscopy; and the colony‐spreading ability of quercetin‐sensitive MRSA, all of which revealed the unique antibacterial properties of quercetin against S. aureus.     

Oxidative Stability in Oil‐in‐Water Emulsions with Quercetin or Rutin Under Iron Catalysis or Riboflavin Photosensitization

The effects of quercetin and rutin on the oxidative stability of oil‐in‐water (O/W) emulsions were tested under riboflavin (RF) photosensitization in the presence or absence of FeCl₂. The degree of oxidation in O/W emulsions was determined by headspace oxygen content, conjugated dienes, and lipid hydroperoxides. Quercetin chelated more metal than did rutin in iron catalyzed O/W emulsions. Generally, 0.1 mM quercetin and rutin was oxidative while 0.5 and 1.0 mM quercetin and rutin was antioxidative in O/W emulsions under RF photosensitization. Depending on the analysis method, the antioxidants had different strengths. The antioxidative or oxidative properties of quercetin and rutin vary in O/W emulsions and depend the quercetin and rutin concentrations and oxidative forces like transition metals, RF photosensitization, or a combination thereof.     

Effects of O-methylated metabolites of quercetin on oxidative stress, thermotolerance, lifespan and bioavailability on Caenorhabditis elegans

Quercetin is a major flavonoid in the human diet and the most commonly used in studies of biological activity. Most of the knowledge about its biological effects has originated from in vitro studies while in vivo data are scarce. Quercetin mostly occurs in foodstuffs as glycosides that are deglycosylated during absorption and further submitted to different conjugation reactions. Methylation to isorhamnetin (quercetin 3'-O-methylether) or tamarixetin (quercetin 4'-O-methylether) seems to be an important conjugation process in quercetin metabolism. In this work, the effects of quercetin and its 3'- and 4'-O-methylated metabolites on the phenotypic characteristics, stress oxidative resistance, thermotolerance and lifespan of the model organism Caenorhabditis elegans have been assessed. The three assayed flavonols significantly prolonged the lifespan of this nematode with an increase from 11% to 16% in the mean lifespan with respect to controls. However, only quercetin significantly increased the reproductive capacity of the worm and enlarged the body size. Exposure to the assayed flavonols also increased significantly the resistance against thermal and juglone-induced oxidative stress, although differences were found depending on the stage of development of the worm. Thus, quercetin offered greater protection when thermal stress was applied in the 1st day of adulthood, whereas tamarixetin was more efficient in worms submitted to stress in the 6th day of adulthood. Similarly, significantly greater protection was provided by quercetin than by its methylated derivatives at the 1st day of adulthood, whilst quercetin and isorhamnetin were equally efficient when the oxidative stress was induced in the 6th of day of adulthood. Further evidence of antioxidant protection was obtained checking the oxidation status of proteins by the OxyBlot? detection kit. Analyses by HPLC-DAD-ESI/MS confirmed that the three flavonols were taken up by C. elegans leading to the formation of some glycosylated, sulfated and methylated metabolites, and that demethylation of these latter to quercetin was also produced. Quantification of the levels of quercetin, isorhamnetin and tamarixetin, as well as their detected metabolites indicated a greater uptake of quercetin than its methylated derivatives by the nematode.     

THE BENEFICIAL EFFECT OF THREE FLAVONOLS AGAINST OXIDATIVE DAMAGE

The ability of three related naturally occurring flavonols in inhibiting Hb oxidation and lipid peroxidation of human erythrocyte membranes was evaluated. The flavonols tested exhibited the following order of potency to inhibit tert‐butyl hydroperoxide‐induced Hb oxidation: quercetin > rutin > morin. The Hb oxidation was estimated by the extent of metHb and hemichrome formation induced by tert‐butyl hydroperoxide. Quercetin or rutin (0.5 mM) increased oxyHb levels about 33% and 10%, respectively. Morin (0.5 mM) was pro‐oxidant, decreasing the oxyHb about 7%. Despite the pro‐oxidant action on Hb oxidation, morin offered greater protection against lipid peroxidation than rutin, preventing the formation of TBA reactive substances by 33.1%, at 0.2 mM. However, quercetin (0.2 mM) provided approximately 50% protection against TBARS formation. The results show that the flavonoids tested are protective for Hb oxidation and lipid peroxidation on erythrocyte membrane subjected to oxidative stress. Quercetin in particular, may be useful in diminishing oxidative damage to red blood cells     

Comparison of Quercetin Pharmacokinetics Following Oral Supplementation in Humans

Abstract: The objective of the study was to investigate the absorption of quercetin aglycone in 18 healthy human subjects administered via the following oral carrier systems: suspension of quercetin (quercetin QU995 powder in Tang^® and spring water), nutritional bars (First Strike?), and chews (RealFX? Q‐Plus?). Subjects were divided into 3 groups of 6 individuals each receiving 500 mg quercetin in one of the aforementioned formulations. Blood levels were monitored immediately pre‐ and for 32 h postadministration. The concentration of total quercetin in blood samples was determined by solid phase extraction followed by high‐performance liquid chromatography analysis. Pharmacokinetic parameters were determined by noncompartmental modeling using Kinetica software. The C_max of quercetin was highest with RealFX? Q‐Plus? Chews (1051.9 ± 393.1 μg/L) achieved within 3.3 h as compared to that for First Strike? Bars (698.1 ± 189.5 μg/L in 2.3 h) and Tang^® suspension (354.4 ± 87.6 μg/L in 4.7 h). The results showed no statistically significant difference in quercetin absorption among groups due to high variability within groups receiving quercetin from same dosage form. This study represents the first comprehensive evaluation of quercetin absorption from quercetin fortified oral food products at doses commonly used for quercetin supplementation. Practical Application: The current study describes for the first time, comprehensive evaluation of quercetin PK in humans from quercetin fortified oral food products at doses commonly used for quercetin supplementation. Owing to quercetin's potent antioxidant and anti‐inflammatory actions, quercetin is widely being used as a nutritional supplement. In order to maximize the bioavailability of quercetin for its use in efficacy studies, it is important to determine its ideal oral carrier system and route for its delivery. The current research unveils vital information about quercetin supplementation to the international community, especially to soldiers, athletes, and the dietary supplement industry.     

Reversal of memory deficits by Coriandrum sativum leaves in mice

BACKGROUND: Coriandrum sativum L., commonly known as coriander and belonging to the family Apiaceae (Umbelliferae), is cultivated throughout the world for its nutritional value. The present study was undertaken to investigate the effects of fresh Coriandrum sativum leaves (CSL) on cognitive functions, total serum cholesterol levels and brain cholinesterase activity in mice. In this study, CSL (5, 10 and 15% w/w of diet) was fed orally with a specially prepared diet for 45 days consecutively to experimental animals. Elevated plus‐maze and passive avoidance apparatus served as the exteroceptive behavioral models for testing memory. Diazepam, scopolamine and ageing‐induced amnesia served as the interoceptive behavioral models. RESULTS: CSL (5, 10 and 15% w/w of diet) produced a dose‐dependent improvement in memory scores of young as well as aged mice. CSL also reversed successfully the memory deficits induced by scopolamine (0.4 mg kg^?1, i.p.) and diazepam (1 mg kg^?1, i.p.). Interestingly, brain cholinesterase activity and serum total cholesterol levels were considerably reduced by CSL administration in daily diets concomitantly for 45 days. CONCLUSION: CSL may be a useful remedy in the management of Alzheimer's disease on account of its multifarious effects such as, memory‐improving property, cholesterol‐lowering property and anticholinesterase activity. Copyright © 2010 Society of Chemical Industry     

Stimulation of AMP‐activated protein kinase and enhancement of basal glucose uptake in muscle cells by quercetin and quercetin glycosides,active principles of the antidiabetic medicinal plant Vaccinium vitis‐idaea

Several medicinal plants that stimulate glucose uptake in skeletal muscle cells were identified from among species used by the Cree of Eeyou Istchee of northern Quebec to treat symptoms of diabetes. This study aimed to elucidate the mechanism of action of one of these products, the berries of Vaccinium vitis idaea, as well as to isolate and identify its active constituents using a classical bioassay‐guided fractionation approach. Western immunoblot analysis in C2C12 muscle cells revealed that the ethanol extract of the berries stimulated the insulin‐independent AMP‐activated protein kinase (AMPK) pathway. The extract mildly inhibited ADP‐stimulated oxygen consumption in isolated mitochondria, an effect consistent with metabolic stress and the ensuing stimulation of AMPK. This mechanism is highly analogous to that of Metformin. Fractionation guided by glucose uptake activity resulted in the isolation of ten compounds. The two most active, quercetin‐3‐O‐glycosides, enhanced glucose uptake by 38–59% (50 μM; 18 h treatment) in the absence of insulin. Quercetin aglycone, a minor constituent, stimulated uptake by 37%. The quercetin glycosides and the aglycone stimulated the AMPK pathway at concentrations of 25–100 μM, but only the aglycone inhibited ATP synthase in isolated mitochondria (by 34 and 79% at 25 and 100 μM, respectively). This discrepancy suggests that the activity of the glycosides may require hydrolysis to the aglycone form. These findings indicate that quercetin and quercetin 3‐O‐glycosides are responsible for the antidiabetic activity of V. vitis crude berry extract mediated by AMPK. These common plant products may thus have potential applications for the prevention and treatment of insulin resistance and other metabolic diseases.     

The biological activities,chemical stability,metabolism and delivery systems of quercetin: A review

BackgroundQuercetin, one of the most well-known flavonoids, has been included in human diet for a long history. The use of quercetin has been widely associated with a great number of health benefits, including antioxidant, anti-inflammatory, antiviral and anticancer as well as the function to ease some cardiovascular diseases (i.e., heart disease, hypertension, and high blood cholesterol). However, poor water solubility, chemical instability and low bioavailability of quercetin greatly limit its applications. Utilization of delivery systems can improve its stability, efficacy and bioavailability.Scope and approachIn this review, biological activities, chemical stability, metabolism and toxicity of quercetin and different delivery systems for quercetin were discussed.Key findings and conclusionsQuercetin digested in human body (e.g., mouth, small intestine, liver, kidneys) undergoes glucuronidation, sulfation or methylation. During the food processing and storage, many factors such as heat, pH, metal ions, could affect the chemical stability (including oxidation and degradation) of quercetin. Utilization of delivery systems including lipid-based carriers, nanoparticles, inclusion complexes, micelles and conjugates-based encapsulation has the potential to improve both the stability and bioavailability and thus health benefits of quercetin. Each delivery system has its unique advantages and shortcomings, and the specific selection should be based on the application domains. Moreover, the exploration of natural food-grade ingredients as main compositions of delivery systems for quercetin might be required in the future.     

Effects of flavonoids on the expression of the pro-inflammatory response in human monocytes induced by ligation of the receptor for AGEs

Increasing evidence has shown advanced glycation end products (AGEs) receptor ligation (RAGE) to be an important part of complex interactions of the oxidative stress and pro-inflammatory responses. In this study, flavonoids were used to monitor the protective effects against the oxidative damage and inflammation mediated by AGEs in human monocytes. S100B (RAGE ligand) treatment in human THP-1 monocytic cells (THP-1) significantly increased gene expression of the pro-inflammatory cytokines TNF-alpha and IL-1beta; chemokines MCP-1 and IP-10; adhesion factors platelet endothelial cell adhesion molecule (PECAM-1) and beta2-integrin; and pro-inflammatory cyclooxygenase-2 (COX-2). S100B treatment with quercetin and catechin in THP-1 cells had inhibitory effects on the expression of pro-inflammatory genes and protein levels. Quercetin and catechin could regulate S100B-activated oxidant stress-sensitive pathways through blocking p47phox protein expression. Treatment with quercetin and catechin could eliminate reactive oxygen species (ROS) to reduce oxidative stress stimulated by S100B in THP-1 cells. Quercetin and catechin also showed different regulatory abilities on mitogen-activated protein kinase (MAPK) signaling pathways by inhibiting protein expression in S100B-stimulated inflammatory responses in THP-1 cells. This study suggests that quercetin and catechin may be of benefit for diabetic vascular complications due to its antioxidant abilities against AGE-mediated oxidative stress through oxidative stress-sensitive and oxidative stress-responsive signaling pathways, which lead to inflammation in human monocytes.     

Identification and in vitro biological activities of flavonols in garlic leaf and shoot: inhibition of soybean lipoxygenase and hyaluronidase activities and scavenging of free radicals

We isolated four flavonols from garlic (Allium sativum L) leaf and shoot and measured the in vitro antioxidant activity of the isolated flavonols and their aglycones. The chemical structures of the compounds were shown to be quercetin 3‐O‐β‐D ‐glucopyranoside (isoquercitrin), quercetin 3‐O‐β‐D ‐xylopyranoside (reynoutrin), kaempferol 3‐O‐β‐D ‐glucopyranoside (astragalin) and isorhamnetin 3‐O‐β‐D ‐glucopyranoside based on FAB‐MS and NMR analyses. Assays of DPPH (1,1‐diphenyl‐β‐picryl hydrazyl) and hydroxyl radical scavenging, inhibition of linoleic acid peroxidation, and soybean lipoxygenase (LO) and hyaluronidase (HYA) inhibition were used to evaluate the antioxidant activity. Quercetin and its glycosides showed the highest antioxidant activity among the compounds. In the LO assay, the IC₅₀ values of quercetin, isoquercitrin and reynoutrin were 16.9, 40.1 and 32.9 µM respectively. Quercetin was the most effective among the flavonols. In the HYA assay the IC₅₀ values of quercetin, isoquercitrin and reynoutrin were 23.0, 20.9 and 22.1 mM respectively. Isoquercitrin had the most potent inhibitory activity on HYA. The inhibition patterns of the flavonols on LO and HYA were elucidated as mixed types of competitive and non‐competitive inhibition according to Lineweaver–Burk plot results. Although most garlic shoots and leaves are discarded and not used at present, our results suggest that ancillary garlic parts could be utilised as functional foods or ingredients. Copyright © 2004 Society of Chemical Industry