Oral Administration Of Quercetin Research Articles

Evaluation of the Mrp2-mediated flavonoid-drug interaction potential of quercetin in rats and in vitro models

Quercetin is a biologically active flavonoid that has been used as a popular health supplement. It is reported that quercetin may cause flavonoid-drug interaction mediated by P-glycoprotein, the most predominant efflux transporter. In this study, we comprehensively evaluated the potential of the pharmacokinetic interaction of quercetin mediated by multidrug resistance-associated protein 2 (MRP2), another major efflux transporter. MRP2-transfected MDCKII cells and LS174T cells were used to evaluate the potential inhibition and induction of MRP2 by quercetin in vitro. To evaluate the induction effect of quercetin on Mrp2 in vivo, Mrp2 mRNA expression in rat liver, kidney, and small intestinal tissues was determined after the oral administration of quercetin (50, 100, or 250 mg/kg) for seven days. Mrp2-mediated interaction potential was also evaluated by the pharmacokinetic study of phenolsulfonphthalein in rats after single or multiple doses of quercetin. Additionally, the effect of quercetin on absorption of docetaxel, a P-glycoprotein and CYP3A4 substrate, was also evaluated. Quercetin inhibited the function of MRP2 at 10 µM and induced the mRNA expression of MRP2 at 50 µM in vitro. Additionally, at 100 mg/kg, quercetin markedly increased Mrp2 expression in the small intestine of rats. However, there was no significant change in phenolsulfonphthalein pharmacokinetics due to single- (50, 100, or 250 mg/kg) or multiple-dose (50, 100, or 250 mg/kg for seven days) quercetin co-administration. By contrast, a significant interaction caused by quercetin (100 mg/kg) was observed in the absorption of docetaxel. The results suggested that although quercetin modulates the function and expression of MRP2 in vitro, it may have a low potential of Mrp2-mediated interaction and present negligible safety concerns related to the interaction.

Improved Oral Absorption of Quercetin from Quercetin Phytosome®, a New Delivery System Based on Food Grade Lecithin.

Background and ObjectivesThe importance of quercetin and flavonoids in the diet and as food supplements is well known, and literature studies support their potential use to treat several human diseases. Many beneficial properties have been described for quercetin, so much effort has been directed into overcoming the major drawbacks of this natural compound—its poor solubility and low oral absorption. The aims of this study were to compare a new food-grade lecithin-based formulation of quercetin, Quercetin Phytosome®, to unformulated quercetin in terms of solubility in simulated gastrointestinal fluids and oral absorption in a randomized crossover pharmacokinetic study of healthy volunteers.MethodsThe solubility of the new formulation was determined by in vitro incubation in simulated gastrointestinal fluids, and quercetin was detected by ultra performance liquid chromatography. A single-dose, randomized, six-sequence/three-period crossover clinical trial (3 × 3 × 3 crossover design) with a balanced carryover effect was conducted in healthy volunteers under fasting conditions. Twelve healthy volunteers of both sexes with an age range of 18–50 years were recruited; one dose of quercetin and two different doses of Quercetin Phytosome were administered orally as film-coated tablets. Pharmacokinetic samples were collected at twelve time points (from 0 h to 24 h) after administration, and quercetin levels were measured by HPLC/MS/MS. Data were analyzed using the Phoenix WinNonlin (v.6.4) software package, and the most significant pharmacokinetic parameters were calculated. Statistical analysis involved performing a two-way ANOVA with repeated measures followed by post hoc analysis (Tukey’s test).ResultsSignificant improvements in both in vitro solubility and oral absorption (in terms of both exposure and maximum concentration achieved) by healthy volunteers in a human clinical study were obtained with the Quercetin Phytosome formulation as compared to unformulated quercetin.ConclusionsA more soluble formulation of quercetin based on lecithin, Quercetin Phytosome, has recently been developed, and was found to facilitate the attainment of very high plasma levels of quercetin—up to 20 times more than usually obtained following a dose of quercetin—when the novel formulation was administered orally in human volunteers, and it did not have any notable side effects. These results suggest that Quercetin Phytosome allows the oral administration of quercetin in a safe and bioavailable manner, thus facilitating the effective utilization of this natural compound to treat various human diseases.

Quercetin protects against chronic prostatitis in rat model through NF-κB and MAPK signaling pathways.

Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a common disease of urology, of which the pathogenesis and therapy remain to be further elucidated. Quercetin has been reported to improve the symptoms of CP/CPPS patients. We aimed to verify the therapeutic effect of quercetin on CP/CPPS and identify the mechanism responsible for it. A novel CP/CPPS model induced with Complete Freund Adjuvant in Sprague Dawley rats was established and the prostates and blood specimens were harvested for further measurement after oral administration of quercetin for 4 weeks. Increased prostate index and infiltration of lymphocytes, up-regulated expression of IL-1β, IL-2, IL-6, IL-17A, MCP1, and TNFα, decreased T-SOD, CAT, GSH-PX, and increased MDA, enhanced phosphorylation of NF-κB, P38, ERK1/2, and SAPK/JNK were detected in CP/CPPS rat model. Quercetin was identified to ameliorate the histo-pathologic changes, decrease the expression of pro-inflammatory cytokines IL-1β, IL-2, IL-6, IL-17A, MCP1, and TNFα, improve anti-oxidant capacity, and suppress the phosphorylation of NF-κB and MAPKs. Quercetin has specific protective effect on CP/CPPS, which is mediated by anti-inflammation, anti-oxidation, and at least partly through NF-κB and MAPK signaling pathways.

The effect of bisphenol A on testicular steroidogenesis and its amelioration by quercetin: an in vivo and in silico approach.

Bisphenol A (BPA), a phenyl ring containing synthetic xenoestrogen, is widely used in the manufacture of polycarbonate plastics, epoxy resins and as a non-polymer additive to other plastics. Food is considered as the main source of exposure to BPA as it leaches out from food containers as well as surface coatings. It causes toxicity in the liver, kidney, brain, and other organs by initiating the process of lipid peroxidation. The present investigation was an attempt to evaluate the effect of BPA on steroidogenesis and its amelioration by quercetin. Inbred Swiss strain male albino mice were orally administered with 80, 120 and 240 mg per kg body weight per day of BPA for 45 days. The results revealed that BPA causes significant (p < 0.05) and dose-dependent changes in the body weight and biochemical parameters like protein, cholesterol and lipid contents as well as activities of 3β-and 17β-hydroxysteroid dehydrogenases in the testis of mice. It was also found to significantly reduce the testosterone level in serum. Oral administration of quercetin (30, 60 and 90 mg per kg body weight per day) along with a high dose of BPA (240 mg per kg body weight per day) for 45 days caused significant amelioration in the body weight and steroidogenesis as compared to the BPA alone treated group. The effect was dose-dependent. This amelioration in BPA-induced toxicity might be due to the antioxidative properties of quercetin. The reduction in the function of enzymes was confirmed by in silico bindings. BPA and quercetin show competitive binding with steroidogenic enzymes as well as binding with each other. This could be a possible mechanism to reduce the toxic effect of BPA which has been supported by molecular dynamics simulations for molecular level recognition with structural insights.

Ameliorative effect of quercetin and rutin via modulation of hypothalamic–Pituitary–Adrenal axis and regulation of fasting glucose in chronic stress-induced prediabetes

Background: Quercetin (QUE) and Rutin (RUT) have nutritive and medicinal values. On the other hand, there are no reports of scientific assessment of its hypothalamo–pituitary–adrenal (HPA) axis modulation in the treatment of prediabetes (DM). Aim: The current study was designed to investigate the modulatory effects of QUE, RUT, and escitalopram (ESC) as antidepressants on HPA axis in chronic stress-induced pre-DM in rats. Materials and Methods: The experimental protocol was of 5 weeks. Chronic unpredictable mild stress (CUMS) was used as a model of depression to induce pre-DM in rats. The treatment was started at the end of 4 th week. After 5 th week, the plasma adrenocorticotropic hormone (ACTH), serum corticosterone (CORT), fasting blood glucose (FBG), and behavioral parameters were evaluated. Results: Oral administration of QUE (50 mg/kg), RUT (50 mg/kg), and ESC (2.5 mg/kg) to stressed control alleviated HPA axis-associated parameters (ACTH and CORT) and significantly decreased the FBG. Besides this, the depressive effects induced by CUMS were significantly improved as evident from results indicating a promising antidepressant activity. Moreover, submaximal dose of QUE (25 mg/kg) and RUT (25 mg/kg) enhanced the antidepressant activity of ESC (1 mg/kg, p.o.), which suggests that they may act through the HPA axis. Conclusion: Current results suggest that chronic stress in rats causes dysregulation of the HPA axis which leads to diabetic-like condition, i.e., “pre-DM.” It is possible that QUE, RUT, and ESC may be able to suppress the HPA axis response which could be beneficial for the treatment of stressed diabetic patients. Abbreviations used: QUE: Quercetin; RUT: Rutin; HPA: Hypothalamic–Pituitary–Adrenal Axis; CUMS: Chronic unpredictable mild stress; ACTH: Adrenocorticotropic hormone; CORT: Corticosterone; FBG: Fasting Blood Glucose; ESC: Escitalopram; FST: Fasting Blood Glucose.

Anti‑inflammatory effect of quercetin and galangin in LPS‑stimulated RAW264.7 macrophages and DNCB‑induced atopic dermatitis animal models.

Flavonols are compounds that have been shown to possess potent anti-inflammatory effects in cellular and animal models of inflammation. In the present study, the anti-inflammatory effects and mechanisms of two natural flavonols, quercetin and galangin, in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages were investigated. It was identified that quercetin and galangin markedly reduced the production of nitric oxide (NO), inducible NO synthase and interleukin-6, and the nuclear translocation of nuclear factor-κB (NF-κB). In addition, LPS-induced activation of extracellular signal-regulated kinase 1/2 (Erk1/2) and c-Jun N-terminal kinase (JNK) was suppressed by quercetin and galangin. Taken together, these data implied that NF-κB, Erk1/2 and JNK may be potential molecular targets of quercetin and galangin in an LPS-induced inflammatory response. Subsequently, the effects of oral administration of quercetin or galangin, either alone or in combination, in a 2,4-dinitrochlorobenzene-induced atopic dermatitis (AD) mouse model were investigated. As a result, measurements of ear thickness and the levels of serum immunoglobulin E, and histological analysis revealed that the two flavonols led to a decrease in inflammation, whereas, in combination, they were even more effective. These results suggested that quercetin and galangin may be promising therapeutic agents for AD. Additionally, their combination may be a novel therapeutic strategy for the prevention of AD.

Quercetin improves endothelial function in diabetic rats through inhibition of endoplasmic reticulum stress-mediated oxidative stress

Endoplasmic reticulum (ER) stress attributes a crucial role in diabetes-induced endothelial dysfunction. The present study investigated the effects of quercetin, a potent antioxidant on the attenuation of ER stress-modulated endothelial dysfunction in streptozotocin (STZ)-induced diabetic rats. Oral administration of quercetin for six weeks to diabetic rats dose-dependently reduced the blood glucose levels and improved insulin secretion. Histopathological examination of pancreatic tissues in diabetic rats showed pathological changes such as shrunken islets, reduction in islet area and distorted β-cells, which were found to be restored by quercetin treatment. In addition, quercetin reduced the pancreatic ER stress-induced endothelial dysfunction as assessed by immunohistochemical analysis of C/ERB homologous protein (CHOP) and endothelin-1 (ET-1). Moreover, quercetin administration progressively increased the expression of vascular endothelial growth factor (VEGF) and its receptor, VEGFR2 in diabetes rats. Quercetin-mediated decrease in the nitric oxide (NO∙) and cyclic 3′,5′- guanosine monophosphate (cGMP) levels were also observed in the diabetic rats. Quercetin treatment reduced the lipid peroxidation in the diabetic rats, meanwhile increased the total antioxidant capacity in the pancreas from diabetic rats. Altogether, these results demonstrated the vasoprotective effect of quercetin against STZ-induced ER stress in the pancreas of diabetic rats.

Quercetin alleviates thermal and cold hyperalgesia in a rat neuropathic pain model by inhibiting Toll-like receptor signaling

Neuropathic pain is caused by lesion or disease of the nervous system, which results in abnormal spontaneous and evoked pain. It’s common in clinical practice and greatly impairs the life quality of patients, but the effective treatment is still lacking. In this study, we aimed to explore the effect of quercetin (QUE) on neuropathic pain and the underlying mechanisms. Spinal nerve ligation (SNL) was performed in Sprague Dawley rats to establish the neuropathic pain model. Single or continuous oral administration of QUE after the operation or continuous administration before the operation was applied to evaluate the effects of QUE on SNL-induced thermal and cold hyperalgesia. Dorsal root ganglions from these rats were harvested to analyze the expression levels of some inflammatory mediators. Primary cultured astrocytes and HEK293 cells were used to further explore the downstream signaling pathways of QUE. Both single and continuous oral administration of QUE dose-dependently alleviated SNL-induced thermal and cold hyperalgesia. Pre-administration also attenuated neuropathic pain symptoms. Meanwhile, SNL-induced increase in protein or mRNA levels of some inflammatory mediators could be down-regulated by QUE treatment. Furthermore, QUE reduced the phosphorylation of TAK1, IKK and JNK2 in cultured astrocytes. Moreover, luciferase assay in HEK293 cells showed that QUE dose-dependently inhibited NF-κB activity only via TAK1. QUE exerts anti-inflammatory effects and alleviates neuropathic pain through the inhibition of Toll-like receptor signaling pathway. It could shed some light on the potential applications of QUE in chronic pain therapy.

Metabolic profiling of quercetin in rats using ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry.

Quercetin, a kind of major flavonoid found in many traditional chinese medicines, is an effective substance for treatments such as lowering blood lipids. However, the studies on quercetin have been mainly focused on its pharmacological effect; the treatment of diseases on a material basis, particularly the metabolites derived from quercetin in vivo, has not been evaluated. In this study, we determined the levels, distributions and types of quercetin's metabolites in plasma, urine, feces and bile of rats after a single oral administration of quercetin at a dose of 80 mg/kg, using ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS). A total of 36 metabolites of quercetin were identified, including 11 metabolites in plasma, 34 metabolites in urine, 12 metabolites in feces and 21 metabolites in bile. The results showed that phase I metabolites were reduction metabolites and phase II metabolites mainly included glucuronidation, sulfation and methylation metabolites. These results provide important information on the metabolism of quercetin, which will be helpful for its further development and utilization.

Quercetin-3-O-glucuronide promotes the proliferation and migration of neural stem cells

Quercetin is a bioactive compound exerting therapeutic effects on in vivo animal models of neurodegeneration or neurotoxicity. However, the narrow therapeutic dose-range of quercetin has been a point of concern since previous studies have demonstrated that quercetin induces cytotoxicity in vitro. Quercetin is metabolized to quercetin glucuronates such as quercetin-3-O-glucuronide (Q3GA), primarily detected in the plasma and the brain. Here, we examined whether and how quercetin or Q3GA regulates neural stem cells (NSCs) in vivo and in vitro. Immunohistochemistry showed that oral administration of quercetin increased nestin-, DCX-, BrdU/DCX-, and BrdU/NeuN-positive cells in the dentate gyrus of mice. However, quercetin decreased the viability of human embryonic NSCs in culture, accompanied by decreased Akt phosphorylation and increased cleavage of caspase-3 and PARP. In contrast, Q3GA increased BrdU-positive cell proliferation, Akt phosphorylation, and cyclin D1 expression. PI3K/Akt inhibitor LY294002 reversed Q3GA-induced Akt phosphorylation and cyclin D1 expression, thereby reducing Q3GA-induced proliferation. Furthermore, Q3GA increased the protein secretion of BDNF and its blockade using anti-BDNF antibody reversed Q3GA-induced proliferation. Under differentiation state, Q3GA promotes NSC migration, along with increased mRNA expression of CXCR4. Moreover, Q3GA significantly reversed scopolamine-induced reduction of Akt phosphorylation in the mouse hippocampus and ameliorated scopolamine-induced memory impairments. Our results demonstrate that quercetin and its metabolite Q3GA control NSC viability in a converse manner through contrary regulation of Akt, accounting for the conflicting effects of quercetin in vivo and in vitro. This study provides a novel mechanism for the positive effects of Q3GA on neurogenesis and suggests its therapeutic potential in neurodegenerative diseases.

Hypoglycemic, Hypolipidemic, and Wound Healing Potential of Quercetin in Streptozotocin-Induced Diabetic Rats.

Background:Among the dietary polyphenolic, quercetin is the most common compound available in vegetables and fruits. The phytochemicals are used to treat diabetic wounds and diabetes, and specifically dietary polyphenols are being extensively studied for their anti-inflammatory and antioxidant abilities.Objective:The objective of the study was to assess the hypoglycemic, hypolipidemic, and wound healing potential of quercetin in streptozotocin (STZ)-induced diabetic Wistar rats.Materials and Methods:Induction of diabetes was done by intraperitoneally administration of STZ at the dose of 55 mg/kg in Wistar rats. An excision wound was created in diabetic rats that were treated with quercetin (100 mg/kg) orally and quercetin ointment topically to evaluate the antidiabetic and wound healing potential of quercetin.Results:Repeated oral administration of quercetin along with topical application of quercetin ointment in diabetic rats normalized the altered blood glucose, hydroxyproline, and glucosamine levels. Topical application of quercetin ointment alone on the excised wound was sufficient enough to heal the wound area in diabetic rats.Conclusions:The result of the present study indicates that quercetin produces hypoglycemic effect in STZ-induced diabetic rats and normalized plasma lipids and protein profiles. Besides, this quercetin also has an excellent wound healing property when applied topically on the wound area in diabetic rats.SUMMARY Quercetin has hypoglycaemic and hypolipidemic potential in streptozotocin induced diabetes in wistar ratsDermal application along with oral administrations of quercetin has more effective in wound healing in diabetic animalsHistopathological studies of pancreas, skin and liver shows significant reduction in archaeological alterations on quercetin administrations in diabetic rats. Abbreviation used: STZ: Streptozotocin; CMC: Carboxy methyl cellulose; HDL: High density lipoproteins; LDL: low density lipoproteins.

Anti-inflammatory Activities and Gastric Ulcer-inducing Properties of Tetraacetylquercetin and Tetrapivaloylquercetin

Quercetin (3,3’4’,5,7-pentahydroxyflavone) has been reported to show anti-inflammatory activity. However, its low oral bioavailability limits the application of quercetin in therapy. Ester derivatives of quercetin have been reported to have higher bioavailability than quercetin. This research aimed to study the anti-inflammatory activities and gastric ulcer-inducing properties of tetraacetylquercetinas well as tetrapivaloylquercetin. Synthesis of tetra-acyl derivatives of quercetin was conducted using acetic anhydride or pivaloyl chloride in the presence of pyridine and the structure was confirmed by 1 H-NMR and 13 C-NMR spectroscopy as well as elemental analysis. At a dose of 20 mg/kg bw, oral administration of quercetin only showed 20% inhibition activity on carragenan induced rat paw edema, while tetraacetyl and tetrapivaloyl derivatives at equimolar dose showed 11-33% and 5-15% inhibition activity respectively. Contrary to the gastric ulcer healing-promoting action of quercetin, tetraacetylquercetin caused mild gastric ulcers. However, no gastric ulcer was observed after administration of tetrapivaloylquercetin. It was concluded that acylation enhances the anti-inflammatory activity of quercetin but causes mild gastric ulcers in the case of tetraacetylation.

Secretory leukoprotease inhibitor is required for efficient quercetin-mediated suppression of TNFα secretion

Dendritic cells (DCs) are professional antigen presenting cells (APCs) that in response to microbial infections generate long-lasting adaptive immune response. Following microbial uptake, DCs undergo a cascade of cellular differentiation that ultimately leads to “mature” DCs. Mature DCs produce a variety of inflammatory cytokines, including tumor necrosis factor-α (TNFα) a key cytokine for the inflammatory cascade. In numerous studies, polyphenols, including quercetin, demonstrated their ability to suppress TNFα secretion and protect from the onset of chronic inflammatory disorders. We show that murine bone marrow derived DCs express Slpi following quercetin exposure. Slpi is known to suppress LPS mediated NFκB activation, thus, it was hypothesized that its expression could be the key step for polyphenol induced inflammatory suppression. Slpi-KO DCs poorly respond to quercetin administration failing to reduce TNFα secretion in response to quercetin exposure. Supernatant from quercetin exposed DCs could also reduce LPS-mediated TNFα secretion by unrelated DCs, but this property is lost using an anti-Slpi antibody. In vivo, oral administration of quercetin is able to induce Slpi expression. Human biopsies from inflamed tract of the intestine reveal the presence of numerous SLPI+ cells and the expression level could be further increased by quercetin administration. We propose that quercetin induces Slpi expression that in turn reduces the inflammatory response. Our data encourages the development of nutritional strategies to improve the efficiency of current therapies for intestinal chronic inflammatory syndrome and reduce the risks of colorectal cancer development.

Quercetin attenuates domoic acid-induced cognitive deficits in mice

Domoic acid (DA) is one of the best known marine toxins, causative of important neurotoxic alterations. DA effects are documented both in wildlife and experimental assays, showing that this toxin causes severe injuries principally in the hippocampal area. Accumulating evidence indicates that mitochondrial dysfunction and oxidative stress are involved in DA-induced cognitive functional impairment. Therefore, therapeutics targeted to improve mitochondrial function and increase oxidative stress defence could be beneficial. Quercetin, a bioflavanoid, has been reported to have potent neuroprotective effects and anti-oxidative ability, but its preventive effects on DA-induced mitochondrial dysfunction and cognitive impairment have not been well characterised. In this study, we evaluated the effects of quercetin on DA-induced cognitive deficits in mice and explored its potential mechanism. Our results showed that the oral administration of quercetin to DA-treated mice significantly improved their behavioural performance in a novel objective recognition task and a Morris water maze task. These improvements were mediated, at least in part, by a stimulation of PPARγ coactivator 1α-mediated mitochondrial biogenesis signalling and an amelioration of mitochondrial dysfunction. Moreover, quercetin activated nuclear factorerythroid-2-related factor-2 (Nrf2)-mediated phase II enzymes and decreased reactive oxygen species and protein carbonylation. Furthermore, the AMP-activated protein kinase (AMPK) activity significantly increased in the quercetin-treated group. Taken together, these findings suggest that a reduction in mitochondrial dysfunction through the increase of AMPK activity, coupled with an increase in Nrf2 pathway mediated oxidative defence, may be one of the mechanisms by which quercetin improves cognitive impairment induced by DA in mice.

Suppression of neuropeptide production by quercetin in allergic rhinitis model rats.

BackgroundQuercetin, a dietary flavonoid found in many fruits, red wine and onion, among others, has been reported to have potent anti-oxidant, anti-viral and anti-cancer effects. Although quercetin is also reported to have anti-inflammatory and anti-allergic effects, the precise mechanisms by which quercetin favorably modify the clinical conditions of allergic diseases such as allergic rhinitis (AR). The present study was designed to examine the influence of quercetin on the development of AR by using AR model rats.MethodsSprague-Dawley (SD) rats were sensitized with toluene 2,4-diisocyanate (TDI) by intranasal instillation of a 10 % TDI in ethyl acetate in a volume of 5 μl once a day for 5 consecutive days. This sensitization procedure was repeated after a 2-day interval. After 5 days of the second sensitization, rats were treated with various doses of quercetin once a day for 2 to 7 days. Nasal allergy-like symptoms, which were induced by bilateral application of 5 μl of 10 % TDI in ethyl acetate, were assessed by counting sneezing and nasal rubbing behaviors for 10 min just after TDI nasal challenge. The levels of substance P (SP), calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) in nasal lavage fluids obtained 6 h after TDI nasal challenge was examined by ELISA.ResultsOral administration of quercetin for 5 and 7 days, but not 2 and 3 days, could inhibit sneezing and nasal rubbing movements, which were increased by TDI nasal challenge. The minimum dose that caused significant inhibition was 25 mg/kg. Oral administration of quercetin at more than 25 mg/kg for 5 days significantly inhibited the increase in SP, CGRP and NGF contents in nasal lavage fluids induced by TDI nasal challenge.ConclusionThe present results strongly suggested that quercetin will be a good candidate for the supplement on the management and treatment of allergic diseases, especially AR.

Quercetin stabilizes apolipoprotein E and reduces brain Aβ levels in amyloid model mice

Apolipoprotein E (apoE) is a major cholesterol carrier that regulates lipid homeostasis by mediating lipid transport from one tissue or cell type to another. In the central neural system (CNS), apoE is mainly produced by astrocytes, and transports cholesterol to neurons via apoE receptors, which are members of the low-density lipoprotein receptor family. The APOEε4 gene is a strong genetic risk factor for late-onset sporadic Alzheimer's disease (AD), likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. ApoE protein levels in cerebrospinal fluid (CSF) and plasma are reduced in APOEε4 carriers and in patients with AD. Furthermore, altered cholesterol levels are also associated with the risk of AD. Aβ accumulation, oligomerization and deposition in the brain are central to the pathogenesis of AD. Mounting evidence demonstrates that apoE and apoE receptors play important roles in these processes. Astrocyte-derived apoE is pivotal for cerebral cholesterol metabolism and clearance of Aβ. Thus, we hypothesized that increased apoE in the brain may be an effective therapeutic strategy for AD. We report here that quercetin can significantly increase apoE levels by inhibiting apoE degradation in immortalized astrocytes. Importantly, we show that oral administration of quercetin significantly increased brain apoE and reduced insoluble Aβ levels in the cortex of 5xFAD amyloid model mice. Our results demonstrate that quercetin increases apoE levels through a novel mechanism and can be explored as a novel class of drug for AD therapy.

Quercetin reduced inflammation and increased antioxidant defense in rat adjuvant arthritis

Novel therapies for rheumatoid arthritis also include the use of naturally occurring compounds possessing antioxidant properties. In the present work, the effects of oral administration of quercetin were investigated in a rat model of adjuvant arthritis. Arthritis was induced by a single intradermal injection of heat-inactivated Mycobacterium butyricum in incomplete Freund's adjuvant. The experimental groups were treated with an oral daily dose of 150 mg/kg b.w. of quercetin for 28 days. Results indicated that quercetin was able to ameliorate all markers of inflammation and oxidative stress measured. Quercetin lowered levels of interleukin-1β, C-reactive protein, and monocyte chemotactic protein-1 and restored plasma antioxidant capacity. In addition, quercetin inhibited the enzymatic activity of pro-inflammatory 12/15-lipoxygenase in lung and liver and increased the expression of heme oxygenase-1 in joint and lung of arthritic rats. Finally, quercetin inhibited the 2-fold increase of NF-қB activity observed in lung, liver and joint after induction of arthritis.

Beneficial effect of quercetin on cholestatic liver injury

Bile duct obstruction and subsequent cholestasis are associated with hepatocellular injury, cholangiocyte proliferation, stellate cell activation, Kupffer cell activation, oxidative stress, inflammation and fibrosis. Flavonoids have been shown to confer beneficial health effects, including hepatoprotection. However, the molecular mechanism of flavonoid-mediated hepatoprotection is incompletely understood. In this study, we report the protective effect of quercetin on cholestatic liver injury. Cholestasis was produced by bile duct ligation (BDL) in male Sprague–Dawley rats for 3weeks. Daily oral administration of quercetin was started 1week before injury and lasted for 4weeks. In comparison with the control group, the BDL group showed liver injury, as evidenced by histological changes, and elevation in serum biochemicals, ductular reaction, fibrosis, inflammation and oxidative stress. These pathophysiological changes were attenuated by daily quercetin supplementation. Quercetin alleviated BDL-induced transforming growth factor beta-1 (TGF-β1), interleukin-1 beta, connective tissue growth factor and collagen expression. The antifibrotic effect of quercetin was accompanied by reductions in α-smooth muscle actin-positive matrix-producing cells and Smad 2/3 activity critical to the fibrogenic potential of TGF-β1. Quercetin also attenuated BDL-induced oxidative stress, leukocyte accumulation, nuclear factor (NF)-κB activation and proinflammatory cytokine production. Further studies demonstrated an inhibitory effect of quercetin on MyD88 and TGF-β-activated kinase-1 critical for linking toll-like receptor (TLR) and NF-κB. Taken together, the hepatoprotective, anti-inflammatory and antifibrotic effects of quercetin seem to be multifactorial. The beneficial effects of daily quercetin supplementation are associated with antioxidative and anti-inflammatory potential as well as down-regulation of NF-κB and TGF-β/Smad signaling, probably via interference with TLR signaling.

Oral administration of quercetin is unable to protect against isoproterenol cardiotoxicity.

Catecholamines are endogenous amines that participate in the maintenance of cardiovascular system homeostasis. However, excessive release or exogenous administration of catecholamines is cardiotoxic. The synthetic catecholamine, isoprenaline (isoproterenol, ISO), with non-selective β-agonistic activity has been used as a viable model of acute myocardial toxicity for many years. Since the pathophysiology of ISO-cardiotoxicity is complex, the aim of this study was to elucidate the effect of oral quercetin pretreatment on myocardial ISO toxicity. Wistar-Han rats were randomly divided into four groups: solvent or quercetin administered orally by gavage in a dose of 10mgkg(-1) daily for 7days were followed by s.c. water for injection or ISO in a dose of 100mgkg(-1). Haemodynamic, ECG and biochemical parameters were measured; effects on blood vessels and myocardial histology were assessed, and accompanying pharmacokinetic analysis was performed. Quercetin was unable to protect the cardiovascular system against acute ISO cardiotoxicity (stroke volume decrease, cardiac troponin T release, QRS-T junction elevation and histological impairment). The sole positive effect of quercetin on catecholamine-induced cardiotoxicity was the normalization of increased left ventricular end-diastolic pressure caused by ISO. Quercetin did not reverse the increased responsiveness of rat aorta to vasoconstriction in ISO-treated animals, but it decreased the same parameter in the control animals. Accompanying pharmacokinetic analysis showed absorption of quercetin and its metabolite 3-hydroxyphenylacetic acid formed by bacterial microflora. In conclusion, a daily oral dose of 10mgkg(-1) of quercetin for 7days did not ameliorate acute ISO-cardiovascular toxicity in rats despite minor positive cardiovascular effects.

Quercetin mitigates lead acetate-induced behavioral and histological alterations via suppression of oxidative stress, Hsp-70, Bak and upregulation of Bcl-2

Lead toxicity is of major health concern due to its persistence in environment that induces cognitive impairment and neuronal degeneration. The present study was conducted to investigate the efficacy of quercetin, a ubiquitous bioflavonoid against lead-induced neurotoxicity in Wistar rats. Briefly, lead acetate (20mg/kg) was injected i.p., followed by oral administration of quercetin (50 and 100mg/kg) once daily for five consecutive days. On 6th day, rats were assessed for motor co-ordination, grip strength and sensorimotor impairment (by adhesive removal test). Lead treated rats have shown marked behavioral impairment with increased oxidative stress. Quercetin reduced lead-induced oxidative burden in brain, thus maintained the normal behavioral functions of lead-intoxicated rats. The lead administered group showed severely vacuolated and pyknotic nuclei with high expressions of Bak and Hsp-70. The expression of anti-apoptotic Bcl-2 was observed to be reduced in lead intoxicated group. Quercetin however, restored the normal morphology of brain and the expressions of Bak, Bcl-2 and Hsp-70. In conclusion, quercetin mitigates the toxic effect of lead effectively and thus, may be an important compound for developing effective therapeutic intervention against metal toxicity.