Quercetin Intake Research Articles

Bioactive compounds and inflammation: an overview

Chronic low-grade inflammation is associated with chronic non-communicable diseases (CNCDs). Bioactive compounds (BC) may influence the reduction of low-grade inflammation. This narrative review highlights the relationship between CNCDs, inflammation, and ingestion of catechins, curcumin, quercetin, and resveratrol. A PubMed research was conducted in the last 10 years. The search was for human studies, and we selected “case reports”; “clinical study”; “clinical trial”; “clinical trial, phase I”; “clinical trial, phase II”; “clinical trial, phase III”; “clinical trial, phase IV”; “comparative study”; “controlled clinical trial”; “multicenter study”; “observational study”; and “randomized clinical trial”. The research was carried out individually for each BC of the diet, and we selected studies related to CNCDs and risk factors for cardiometabolic diseases. The keywords used were “catechin,” “curcumin,” “quercetin,” and “resveratrol”, in addition to “inflammation.” There are no recommendations for BC intake. The studies in this review analyzed different doses, forms of presentation, clinical conditions, and periods of supplementation. Most articles on catechin, curcumin, and quercetin had a clear beneficial relationship between inflammation, CNCDs, and risk factors for cardiometabolic diseases. On the other hand, studies on resveratrol are inconclusive. Some studies have shown beneficial effects of BC; however, the studies are not conclusive. In different situations, BC have no significant effects, and, at other times, they may even have a detrimental effect. Further studies are needed to establish which dose produces beneficial health effects and which clinical conditions can benefit from the intake of dietary sources from these BC.

The Effects of Quercetin on High Fat Diet-Induced Inflammation and Oxidative Stress in Brown Adipose Tissue

Abstract Objectives Under obesity state, adipose tissue derived inflammatory mediators circulate all over the body and induce low-grade chronic inflammation, which is the main cause for the development of metabolic diseases. Moreover, inflammation-induced reactive oxygen species (ROS) cause oxidative stress, a process in damaging cellular structure and functions. Recently, microRNAs (miRNAs) were found to potentially regulate inflammation and its associated diseases. Brown adipose tissue (BAT) protects against obesity through thermogenic activity to increase energy expenditure. However, high levels of inflammation, ROS generation and aberrant level of miRNAs result in the dysfunction of BAT. Previously, quercetin showed anti-obesity effect through BAT activation. Thus, the purpose of this study was sought to investigate the effect of quercetin on high fat diet (HFD)-induced inflammation and oxidative stress in BAT. Methods C57BL/6 male mice were fed with a HFD or HFD supplemented with 1% quercetin (HFDQ) for 16 weeks. Total RNA was isolated from BAT to measure the expression of target mRNAs such as tumor necrosis factor alpha (TNFa), interleukin (IL) 1b, IL6, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX) 2, NADPH oxidase (NOX) 2, nuclear factor E2-related factor (NRF) 2, superoxide dismutase (SOD) 2, SOD3, and catalase that are involved in regulation of inflammation and oxidative stress, and microRNA (miRNA)-155, a master regulator of inflammation, using a quantitative PCR. Results BAT of HFDQ-fed mice exhibited decreased expression of COX2, TNFa, IL1b, IL6, and iNOS compared to that of HFD-induced obese mice. NOX2 gene encoding an enzyme that generates ROS was also decreased in BAT of HFDQ-fed mice. The genes such as SOD2, SOD3, NRF2, and catalase that are involved in regulation of antioxidant enzymes were significantly increased. As the cognate gene of TNFa, miRNA-155 levels were downregulated. Conclusions Quercetin ameliorates HFD-induced inflammation and oxidative stress in BAT by regulating miRNA-155. Intake of quercetin may improve obese conditions by regulating BAT function through anti-inflammatory and antioxidant effects. Funding Sources This work was supported by USDA.

Quercetin Is a Flavonoid Breast Cancer Resistance Protein Inhibitor with an Impact on the Oral Pharmacokinetics of Sulfasalazine in Rats.

The potential inhibitory effect of quercetin, a major plant flavonol, on breast cancer resistance protein (BCRP) activity was investigated in this study. The presence of quercetin significantly increased the cellular accumulation and associated cytotoxicity of the BCRP substrate mitoxantrone in human cervical cancer cells (HeLa cells) in a concentration-dependent manner. The transcellular efflux of prazosin, a stereotypical BCRP substrate, was also significantly reduced in the presence of quercetin in a bidirectional transport assay using human BCRP-overexpressing cells; further kinetic analysis revealed IC50 and Ki values of 4.22 and 3.91 μM, respectively. Moreover, pretreatment with 10 mg/kg quercetin in rats led to a 1.8-fold and 1.5-fold increase in the AUC8h (i.e., 44.5 ± 11.8 min∙μg/mL vs. 25.7 ± 9.98 min∙μg/mL, p < 0.05) and Cmax (i.e., 179 ± 23.0 ng/mL vs. 122 ± 23.2 ng/mL, p < 0.05) of orally administered sulfasalazine, respectively. Collectively, these results provide evidence that quercetin acts as an in vivo as well as in vitro inhibitor of BCRP. Considering the high dietary intake of quercetin as well as its consumption as a dietary supplement, issuing a caution regarding its food–drug interactions should be considered.

Pharmacological Activity of Quercetin and 5 Caffeoylquinic Acid Oral Intake in Male Balb/c Mice with Lung Adenocarcinoma

Lung adenocarcinoma (LAC) is a major worldwide cause of death by cancer, it shows high aggressiveness, functional decline, systemic compromise and severe cachexia, which might be counteracted by dietary redox-active phytochemicals. Therefore, our aim was to establish the anticancer effects of the oral intake of quercetin and 5 caffeoylquinic acid. LAC-1-bearing male Balb/c mice received quercetin (0-25μg/kg/d) and 5 caffeoylquinic acid (0-120μg/kg/d) for three weeks, with different organic and biochemical variables being then compared with ANOVA and the Fisher Test (p<0.05). Quercetin delayed 1.18 fold tumour appearance and increased 8.87 fold non-neoplastic body weight gain, whereas 5 caffeoylquinic acid did it in a lesser extent (1.17 and 2.48 fold, respectively), with tumour weight being consequent with the evolution time. Quercetin induced >1.15 fold tumour hydroperoxides and lipoperoxides, whereas 5 caffeoylquinic acid induced only lipoperoxides. Although both phytochemicals reduced <0.85 fold hydroperoxides and lipoperoxides in the kidney, only quercetin was also antioxidant in the liver. Additionally, 5 caffeoylquinic acid increased >1.15 fold hepatic and renal weights. Although these phytochemicals did not modify telencephalic interleukin 6 production, quercetin augmented 2.51 fold interleukin 6 in the diencephalon, whereas 5 caffeoylquinic acid decreased it 0.43 fold. Quercetin delayed lung adenocarcinoma appearance and increased the non-neoplastic body weight gain in mice with tumour oxidative stress, without brain interleukin 6 participation. 5 caffeoylquinic acid showed similar effects, although they were weaker. Additionally, quercetin acted as a hepatic and renal antioxidant, whereas 5 caffeoylquinic acid only exerted this effect in the kidney. Therefore, safe oral doses of this flavonoid are promissory to modulate lung cancer progression, with further studies being encouraged.

The Effect of Corchorus olitorius L. Extract on Viability of Breast Cancer Cells: A friend or a foe?

This Corchorus olitorius L. is known to be a medicinal plant widely consumed in the Eastern Mediterranean region and has anti-bacterial, anti-inflammatory and anti-cancer properties. Breast cancer has one of the highest mortality rates among all cancers. Therefore, the main aim of the study is to evaluate the effectiveness of C. olitorius plant on viability of estrogen receptor (ER) positive breast cancer cell line, MCF-7. C. olitorius leaves first extracted with ethanol, then LC-MS/MS analysis was done for identification of phytochemicals. MTT assay was used for assessment of cell viability of MCF-7 cells. Cells were treated with C. olitorius extracts at five concentrations (5, 10, 20, 50, 100 µg/ml) and four different incubation periods (24, 48, 72, 96 h). LC-MS/MS analysis identified seven phytochemicals in the extract, mainly quercetin and caffeoylquinic acid derivatives. MTT results showed that the extract was only slightly effective in terms of reduction of cell viability at 50 and 100 µg/ml doses which were incubated for 24 and 48 h. Lower concentration doses did not show any effect in cell viability of MCF-7 cells. Longer incubation periods tend to increase cell viability of breast cancer cells. Quercetin identified within the extract might interfere with ER and promote MCF-7 cell proliferation. Therefore, in ER positive breast adenocarcinoma, quercetin intake and doses should carefully be monitored. More studies regarding the relationship between C. olitorius , quercetin and breast cancer should be done for further clarification of the topic.

Study of Ultrasound-assisted Acid Hydrolysis to Obtain Quercetin and their Antioxidant Activities from some Plants

In this study, acidic hydrolysis to release the aglycone quercetin from plant extracts under ultrasound-assisted conditions was investigated. Based on the stability of quercetin, the suitable conditions were as follows: methanol/H2O (50:20, v/v) was added to the powder plants (ratio 50:1, ml/g), these mixtures were placed in ultrasonic bath of 37 kHz/550W; kept at 70°C within 30 min and then filtered. The filtrate was acidified with HCl (70:8, ml/ml). Lastly, the ultrasonication was carried out for hydrolysis for 1 hour (the second ultrasound) to obtain quercetin. We have obtained quercetin containing hydrolyzed extract from 10 plants to determine quercetin concentrations (using the HPLC optimized conditions) and evaluate the antioxidant activity (the capability to scavenge the DPPH radical). In 10 samples of plants that were obtained, both quercetin concentrations and antioxidant activity in the plant extract of the flower buds of Sophora japonica L have the highest value, then to the plant extract of Nelumbo nucifera Gaertn. In the Sophora flower-bud and the lotus leaf, quercetin content is calculated on dry material (mg/100g), 15423.04 and 5190.82 respectively; the average percentage inhibition of DPPH 100 µM (%) 55.26% and 32.23%., respectively.&#x0D; Keywords: Quercetin, HPLC, acid hydrolysis, ultrasound-assisted, antioxidant activity.&#x0D; References&#x0D; [1] S.G. Dmitrienko, V.A. Kudrinskaya, V.V. Apyari, Methods of extraction, preconcentration, and determination of quercetin, Journal of Analytical Chemistry 67 (4) (2012) 299-311. https://doi.org/ 101134/S106193481204003X.[2] H. Nishimuro, H. Ohnishi, M. Sato, M. Ohnishi-Kameyama, I. Matsunaga, S. Naito, K. Ippoushi, H. Oike, T. Nagata, H. Akasaka, S. Saitoh, K. Shimamoto, M. Konori, Estimated daily intake and seasonal food sources of quercetin in Japan, Nutrients 7 (4) (2015) 2345-2355. https://doi.org/ 10.3390/nu7042345.[3] C. Zhao, X. Ren, C. Li, H. Jiang, J. Guan, W. Su, Y. Li, Y. Tian, T. Wang, S. Li, Coupling ultrasound with heat-reflux to improve the extraction of quercetin, kaempferol, ginkgetin and sciadopitysin from Mairei Yew leaves, Applied Sciences 9 (4) (2019) 795-810. https://doi.org/10.3390/app9040795.[4] J. Azmir, M.S.I. Zaidul, M.M. Rahman, K.M. Sharif, A. Mohamed., F. Sahena, A.H.M. Jahurul, K. Ghafoor, N.A.N. Norulain, K.A.M. Omar, Techniques for extraction of bioactive compounds from plant materials : A review, Journal of Food Engineering 117 (4) (2013) 426-434. https://doi. org/10.1016/j.jfoodeng.2013.01.014.[5] L.H. Hoang, D.T.H. Anh, D.T. Hue, T.T.K. Oanh, N.Q. Huy, Determination of Quercetin Aglycone in Flos Sophorae japonicae Extract by High Performance Liquid Chromatography, VNU Journal of Science: Natural Sciences and Technology 33 (1S) (2017) 214-223 (in Vietnamese). https://doi.org/10.25073/2588-1140/ vnunst.4534. [6] A.M. Nuutila, K. Kammiovirta, M. Oksman-Caldentay, Comparison of methods for the hydrolysis of flavonoids and phenolic acids from onion and spinach for HPLC analysis, Food Chemistry 76 (4) (2002) 519-525. https://doi.org/ 10.1016/S0308-8146(01)00305-3.[7] L. Qiao, Y. Sun, R. Chen, Y. Fu, W. Zhang, X. Li, J. Chen, Y. Shen, X. Ye, Sonochemical effects on 14 flavonoids common in citrus : Relation to stability, Plos One 9 (2) (2014) e87766. https://doi. org/10.1371/journal.pone.0087766.[8] W. Brand-Williams, M.E. Cuvelier, C. Berset, Use of a free radical method to evaluate antioxidant activity, LWT - Food Science and Technology 28 (1995) 25-30. https://doi.org/10.1016/S0023-6438 (95)80008-5.&#x0D; [9] M. Biesaga, Influence of extraction methods on stability of flavonoids, Journal of Chromatography A 1218 (2011) 2505-2512. https://doi.org/10.1016/ j.chroma.2011.02.059.[10] L. Paniwnyk, E. Beaufoy, J.P. Lorimer, T.J. Manson, The extraction of rutin from flower buds of Sophora japonica, Ultrasonics Sonochemistry 8 (3) (2001) 299-301. https://doi.org/10.1016/S1350 -4177(00)00075-4.[11] X. He, Y. Bai, Z. Zhao, X. Wang, J. Fang, L. Huang, M. Zeng, Q. Zhang, Y. Zhang, Z. Zheng, Local and traditional uses, phytochemistry, and pharmacology of Sophora japonica L.: A review, Journal of Ethnopharmacology 187 (2016) 160-182. https://doi.org/10.1016/j.jep.2016.04.014.[12] I.Y. Bae, B.Y. Kwak, H.G. Lee, Synergistic antiradical action of natural antioxidants and herbal mixture for preventing dioxin toxicity, Food Science and Biotechnology 21 (2) (2012) 491-496. https://doi.org/10.1007/s10068-012-0062-9.

Dietary Quercetin and Kaempferol: Bioavailability and Potential Cardiovascular-Related Bioactivity in Humans.

Fruit and vegetable intake has been associated with a reduced risk of cardiovascular disease. Quercetin and kaempferol are among the most ubiquitous polyphenols in fruit and vegetables. Most of the quercetin and kaempferol in plants is attached to sugar moieties rather than in the free form. The types and attachments of sugars impact bioavailability, and thus bioactivity. This article aims to review the current literature on the bioavailability of quercetin and kaempferol from food sources and evaluate the potential cardiovascular effects in humans. Foods with the highest concentrations of quercetin and kaempferol in plants are not necessarily the most bioavailable sources. Glucoside conjugates which are found in onions appear to have the highest bioavailability in humans. The absorbed quercetin and kaempferol are rapidly metabolized in the liver and circulate as methyl, glucuronide, and sulfate metabolites. These metabolites can be measured in the blood and urine to assess bioactivity in human trials. The optimal effective dose of quercetin reported to have beneficial effect of lowering blood pressure and inflammation is 500 mg of the aglycone form. Few clinical studies have examined the potential cardiovascular effects of high intakes of quercetin- and kaempferol-rich plants. However, it is possible that a lower dosage from plant sources could be effective due to of its higher bioavailability compared to the aglycone form. Studies are needed to evaluate the potential cardiovascular benefits of plants rich in quercetin and kaempferol glycoside conjugates.

2228-PUB: Meta-analysis of Recent Data from Several Independent Sources Suggests That Methylgloxal (MGO) Is Trapped by Dietary Flavonoids and Excreted in Urine as MGO-Flavonoid Adducts

Methylglyoxal (MGO) is a reactive α-dicarbonyl produced as an unavoidable byproduct of glycolysis. Because it reacts readily with amino acids, nucleic acids and ethanolamine in phospholipids, MGO is deleterious to living systems and contributes significantly to diabetic complications. The primary defense against MGO is the glyoxalase system that oxidizes MGO to D-lactate. However, about 1% of MGO evades this mechanism and remains free to react with susceptible biomolecules. Consequently MGO, whose concentrations increase chronically in diabetics and temporarily in all individuals after meals, leads to increasing production of Advanced Glycation Endproducts (AGE) in diabetes and aging. Several recent papers suggest that residual MGO, can be trapped by scavengers with the resulting adduct safely removed via the urinary system One such report is Metformin, a drug that not only reduces blood glucose but is also beneficial for cardiovascular health and lowers mortality. In 2016 Kinsky et al. showed that Metformin reacts with MGO in diabetics and the adduct is eliminated in urine. This MGO-scavenging activity is also seen with some endogenous amine-containing compounds such as carnosine, taurine and creatine. In addition to metformin and other amine-based scavengers, there is solid evidence that phytochemicals, such as flavonoids in fruit and vegetables, are also MGO scavengers. Most recently Schalkwjik et al. have published data showing that modest ingestion of quercetin, reduces MGO in plasma by 10%. Prior to that, Sang et al. have shown that three other polyphenols: genistein, 6-shagaol and epicatechin, react with MGO in mice and are subsequently excreted as covalent adducts in urine. These studies can be interpreted in many ways, however the simplest interpretation may be that scavenging of MGO and its elimination may account, in part, for the widely reported positive effects of flavonoids on human health. Disclosure B. Szwergold: None. C.B. Miller: None.

Correlations between urinary concentrations and dietary intakes of flavonols in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

In this study, we aimed to study the correlation between acute and habitual intakes of flavonols, their main food sources and their 24-h urinary concentrations in an European population. A 24-h dietary recall (24-HDR) and 24-h urine samples were collected on the same day from a convenience subsample of 475 men and women from four countries (France, Italy, Greece and Germany) of the European Prospective Investigation into Cancer and Nutrition (EPIC) study. A standardized 24-HDR software and a country/centre-specific validated dietary questionnaire (DQ) were used to collect acute and habitual dietary data, respectively. The intake of dietary flavonols was estimated using the Phenol-Explorer database. Urinary flavonols (quercetin, isorhamnetin, and kaempferol) were analysed using tandem mass spectrometry with a previous enzymatic hydrolysis. Weak partial Spearman correlations between both dietary acute and habitual intake and urinary concentrations of quercetin (both Rpartial ~ 0.3) and total flavonols (both Rpartial ~ 0.2) were observed. No significant correlations were found for kaempferol and isorhamentin. Regarding flavonol-rich foods, weak correlations were found between urinary concentrations of quercetin and total flavonols and the acute intake of onions and garlics, fruits, tea, and herbal tea (all Rpartial ~ 0.2). For habitual intake, statistically significant correlations were only found between urinary quercetin concentration and herbal tea (Rpartial = 0.345) and between urinary total flavonol concentration and tea, and herbal tea consumption (Rpartial ~ 0.2). Our results suggest that urinary quercetin level can be used as potential concentration biomarkers of both acute and habitual quercetin intake, while urinary concentrations of flavonols are unlikely to be useful biomarkers of individual flavonol-rich foods.

Clinical effectiveness of quercetin supplementation in the management of weight loss: a pooled analysis of randomized controlled trials.

Purpose: The previous investigations which considered the possible effect of the quercetin supplementation for overweight and obesity have led to inconsistent results. Here, we aimed to evaluate the effects of quercetin on weight loss using a meta-analysis of randomized controlled clinical trials (RCTs).Methods: Relevant studies were systematically searched from the MEDLINE, EMBASE, Google Scholar, and Scopus databases. RCTs that investigated the effects of quercetin on weight loss in humans were included for quality assessment, meta-analyses, sensitivity analysis, subgroup analyses, and publication bias assessment. Effect size was expressed as weighted mean difference (WMD) and 95% CI by using a random-effects model. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to rate the level of evidence.Results: Nine RCTs (11 treatment arms) with 525 participants were finally included for data pooling. Our meta-analysis revealed that daily quercetin supplementation did not significantly affect the body weight (WMD: −0.35 kg, 95% CI: −2.03, 1.33; P=0.68), body mass index (WMD: −0.04 kg/m2, 95% CI: −0.54, 0.45; P=0.87), waist circumference (WMD: −0.37 cm, 95% CI: −1.81, 1.06; P=0.61), and waist to hip ratio (WMD: −0.01, 95% CI: −0.03, 0.01; P=0.48). Subgroup analysis could not identify factors significantly influencing these parameters. These results were robust in sensitivity analysis, and no significant publication bias was found.Conclusion: The current evidence suggests that quercetin intake did not show a notably favorable effect on weight loss. Future well-designed and long-term clinical trials are required to confirm these results.

Quercetin mitigates anxiety-like behavior and normalizes hypothalamus-pituitary-adrenal axis function in a mouse model of mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is a major public health risk for developing anxiety-related disorders and hypothalamus-pituitary-adrenal (HPA) axis dysregulation in humans. Extensive research has shown that dietary intake or supplementation of the natural flavonoid quercetin might be useful for treating anxiety-related symptoms. The objectives of this study were to determine whether quercetin treatment can attenuate anxiogenic-like behaviors and normalize HPA axis function in mice with mTBI. Animals subjected to mTBI were treated daily with quercetin (50 mg/kg) or diazepam (positive control, 3 mg/kg) for 14 days. Four behavioral tests (open field, plus maze, light-dark box, and zero maze) were used to assess anxiety-related behaviors in mice. To evaluate HPA axis function, adrenocorticotropic hormone and corticosterone were measured in the serum of mice after the anxiety tests. Quercetin treatment was found to significantly reduce anxiety-like behaviors in mTBI-induced mice. A strength of this study is the consistency of results among anxiety tests. The dysregulation of the HPA axis in mTBI-induced mice treated with quercetin was also attenuated, with decreased levels of adrenocorticotropic hormone and corticosterone. The effects of quercetin were comparable with those of diazepam treatment. Taken together, these results suggest that quercetin might be useful for treating anxiety-related symptoms and HPA axis hyperreactivity in patients with mTBI.

Maternal quercetin intake during lactation attenuates renal inflammation and modulates autophagy flux in high-fructose-diet-fed female rat offspring exposed to maternal malnutrition.

Maternal restriction of dietary proteins during pregnancy and lactation is known to induce renal disease in later life. High fructose intake causes metabolic syndrome, which results in an increased risk of chronic kidney disease development. We investigated whether quercetin intake during lactation affects high-fructose-diet-induced inflammation and autophagy flux in the kidneys of high-fructose-diet-fed adult female offspring exposed to maternal normal-protein (NP) or low-protein (LP) diets. Pregnant Wistar rats received diets containing 20% (NP) or 8% (LP) casein, and 0 or 0.2% quercetin containing NP diets (NP/NP or NP/NPQ) in experiment (Expt.) 1 and 0 or 0.2% quercetin containing LP diets (LP/LP or LP/LPQ) in Expt. 2 during lactation. At weaning, pups that received a diet of distilled water (Wa) or 10% fructose solution (Fr) were divided into six groups: NP/NP/Wa, NP/NP/Fr, NP/NPQ/Fr in Expt. 1, and LP/LP/Wa, LP/LP/Fr, LP/LPQ/Fr in Expt. 2. At week 12, macrophage infiltration, mRNA levels of TNF-α and IL-6, and markers of autophagy flux in the kidneys of male offspring were examined. We found that macrophage number and, TNF-α and IL-6 mRNA levels increased in the kidneys of the NP/NP/Fr or LP/LP/Fr, respectively. Conversely, macrophage number and IL-6 levels in the NP/NPQ/Fr or LP/LPQ/Fr decreased. LC3B-II levels were downregulated in the NP/NP/Fr or LP/LP/Fr rats. In contrast, LC3B-II levels were upregulated, while p62 levels were downregulated in the NP/NPQ/Fr and LP/LPQ/Fr rats. In conclusion, maternal quercetin intake during lactation may cause long-term alterations in inflammation and autophagy flux in the kidneys of high-fructose-diet-fed adult female offspring.

15 - Role of polyphenolic flavonoid and exercise in atherosclerosis

Introduction Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in USA and Western world. Polyphenolic compounds are present in our daily diet such as vegetable, fruit, onion, and processed food such as red wine, and dark chocolate. Flavonoids, a member of polyphenols and related compounds have significant antioxidant and anti-inflammatory activity, which could vary based on their structures. Recent studies indicated that quercetin; a flavonol reduces the health risks linked with obesity, heart disease, diabetes and high blood pressure. The objective: This study is designed to investigate the effects of quercetin intake and exercise in atherosclerosis. Study Design The study compares the effect of intake of quercetin with exercise on atherosclerotic plaque and biomarkers of atherosclerosis. We conducted three separate studies as follows: Study 1: C57BL6 wild type female mice (N=35). Study 2: C57BL6 wild type male mice (N=40) and Study 3: C57BL6 LDLr -/- mice (N=40). Mice were fed normal mouse chow or atherogenic diet and orally supplied with 100 μg/day of quercetin with or without exercising. In each study animals were divided into four groups (10 each). These groups were as follows: Control mice, left untreated; control quercetin group, exercise group without quercetin, and exercise group with quercetin supplements. The exercise groups were run on a treadmill for 30 minutes, 15-30 m/m/ 5 days/week for 30-60 days. At the end of the 1-2 month of treatment, mice were sacrificed. Livers, aortas, adipose tissue and blood were collected. Plasma lipids, and inflammatory biomarkers, and liver and aorta gene expressions and western blot were performed. Results In wildtype males lipids modulators such as PCSK9 mRNA levels were significantly up-regulated with combination of exercise and quercetin intake (p

Estimated daily quercetin intake and association with the prevalence of type 2 diabetes mellitus in Chinese adults.

Quercetin is one of potential antidiabetic substances because of its powerful antioxidant and anti-inflammatory actions. The purpose of this study is to estimate daily quercetin intake and assess the relationship between dietary quercetin intake and the prevalence of type 2 diabetes mellitus (T2DM) in a Chinese population. Dietary intake was investigated by a validated 100-item food frequency questionnaire. Daily intakes of quercetin and nutrients were calculated accordingly. T2DM was diagnosed based on the criteria of the American Diabetes Association. Adjusted logistic regression models were used to analyze the relationship between the quartiles of quercetin intake and the prevalence of T2DM. The prevalences of T2DM were 8.35% in men and 4.68% in women. The main food sources of quercetin were apple, orange, and green tea. Daily intake of quercetin was 20.9 ± 2.32mg/day (mean ± SD). After adjusting for potentially confounding factors, the odds ratios (95% CI) for T2DM across the ascending quartiles of quercetin intake were: 1.00 (reference), 0.75 (0.60-0.95), 0.76 (0.59-0.99), and 0.63 (0.51-0.94). The results of the present study showed that quercetin intake was inversely related to the prevalence of T2DM in the Chinese population, suggesting a protective effect of quercetin in the development of T2DM.

The acute effect of Quercetin on muscle performance following a single resistance training session.

To examine the effect of acute quercetin (Q) ingestion on neuromuscular function, biomarkers of muscle damage, and rate of perceived exertion (RPE) in response to an acute bout of resistance training. 10 young men (22.1 ± 1.8 years, 24.1 ± 3.1 BMI) participated in a randomized, double-blind, crossover study. Subjects consumed Q (1g/day) or placebo (PLA) 3h prior to a resistance training session which consisted of 3 sets of 8 repetitions at 80% of the one repetition maximum (1RM) completed bilaterally for eight different resistance exercises. Electromyographic (EMG) signals were recorded from the knee extensor muscles during maximal isometric (MVIC) and isokinetic voluntary contractions, and during an isometric fatiguing test. Mechanical and EMG signals, biomarkers of cell damage, and RPE score were measured PRE, immediately POST, and 24h (blood indices only) following the resistance exercise. After a single dose of Q, the torque-velocity curve of knee extensors was enhanced and after the resistance exercise, subjects showed a lower MVIC reduction (Q: 0.91 ± 6.10%, PLA: 8.66 ± 5.08%) with a greater rate of torque development (+ 10.6%, p < 0.005) and neuromuscular efficiency ratio (+ 28.2%, p < 0.005). Total volume of the resistance exercises was significantly greater in Q (1691.10 ± 376.71 kgrep) compared to PLA (1663.65 ± 378.85 kgrep) (p < 0.05) with a comparable RPE score. No significant differences were found in blood marker between treatments. The acute ingestion of Q may enhance the neuromuscular performance during and after a resistance training session.

Quercetin ameliorates HFD-induced NAFLD by promoting hepatic VLDL assembly and lipophagy via the IRE1a/XBP1s pathway

The consumption of a quercetin-rich diet has been well-established as a feasible method against non-alcoholic fatty liver disease (NAFLD); however, the molecular mechanisms underlying the progression of NAFLD and its intervention by quercetin remain largely obscure. Male Sprague-Dawley rats fed high-fat diet (HFD), and HepG2 cells stimulated with free fatty acid, were treated with quercetin and various pharmacological reagents to explore the effect of signaling pathways involved in endoplasmic reticulum stress on very low-density lipoprotein (VLDL) assembly and lipophagy. Quercetin intake decreased hepatic TG content by 39%, with a 1.5-fold increase in VLDL, and up-regulated spliced X-box binding protein 1 (XBP1s) expression compared with the HFD group. Thapsigargin or STF-083010 (an IRE1α endonuclease inhibitor) decreased VLDL content in a dose-dependent manner, partially counteracting the protective effects of quercetin, 4-PBA or APY-29 (an IRE1α endonuclease activator). Additionally, microsomal TG-transfer protein complex expression was increased with quercetin-treated and down-regulated by STF-083010. Moreover, quercetin increased co-localization of lysosomes with lipid droplets (LDs) accompanied by decreased p62 accumulation. STF-083010 partially abolished the effect of quercetin on LDs autophagy in an mTOR-independent manner. Collectively, these findings demonstrate that hepatic VLDL assembly and lipophagy are the main targets of quercetin against NAFLD via the IRE1a/XBP1s pathway.

Quercetin exerts cardiovascular protective effects in LPS-induced dysfunction in vivo by regulating inflammatory cytokine expression, NF-κB phosphorylation, and caspase activity.

Impaired myocardial contractile function, one of the well-documented features of sepsis, contributes greatly to the high rate of mortality. Quercetin is widely accepted as a potential antioxidant and free radical scavenger. Epidemiologic studies have suggested that an increase in the intake of dietary Quercetin can reduce the risk of cardiac disease. However, presently there is no report yet on the influence of Quercetin on LPS-induced myocardial dysfunction in vivo. Cardiovascular protective effects of Quercetin on LPS-induced sepsis in mice were measured after intragastric administration, using normal saline as a positive control. Quercetin pretreatment significantly alleviated LPS-induced cardiac abnormalities in mice. The histopathologic findings in the present study justify the findings reported from the biochemical analyses. Our observation from the present research work reveals that Quercetin suppressed the production of proinflammatory cytokines at different levels, such as TNF-α and IL-1β, and inhibits the activation of I-κB phosphorylation, whereas the total content was not affected. Apoptotic pathways are related to Quercetin protection in the development of myocardial dysfunction. In conclusion, our findings demonstrate the adjuvant potentials of Quercetin for clinical sepsis treatment.

Pharmacological Effect of Quercetin in Hypertension and Its Potential Application in Pregnancy-Induced Hypertension: Review of In Vitro, In Vivo, and Clinical Studies.

Since improving maternal and child health is a public health priority worldwide, the main aim of treatment of hypertension in pregnant women is to prevent complications during pregnancy, labor, and postpartum. In consequence, much attention is paid to the use of antihypertensive drugs that can be used safely during pregnancy. Several side effects of methyldopa, which is currently the most commonly used antihypertensive drug in pregnant women, mean that the search for an effective and safe alternative still continues. Flavonoid compounds present in medicinal plants, vegetables, and fruits may be a promising source of new drugs. In this aspect, quercetin, a well-known flavonoid due to its antihypertensive action, may be considered a prototype for safe antihypertensive drugs. This review focuses on the selective activity of quercetin. Based on recent studies, a few problems were discussed, including (1) pathology of pregnancy-induced hypertension; (2) search for new pharmacological treatments of pregnancy-induced hypertension; (3) issues with the use of herbal extracts during pregnancy; (4) flavonoids as natural active chemical compounds; (5) quercetin: its action during pregnancy, in vitro and in vivo pharmacological activities, clinical trials, and meta-analysis; (6) quercetin intake during pregnancy; (7) other natural compounds tested during pregnancy; (8) potential problems with the use of quercetin; (9) safety profile of quercetin. Various studies have shown a beneficial effect of quercetin on vascular endothelial function and its antioxidative and anti-inflammatory activity on cellular and tissue level. It is known that in animal models quercetin affects positively the development of embryo, fetus, and placenta. Because this flavonoid did not have teratogenic and abortive effect, it is generally recognized as safe. For this reason it should be appreciated and studied in the aspect of its potential use in the prevention and treatment of pregnancy-induced hypertension among women in this risk group.

Safety Aspects of the Use of Quercetin as a Dietary Supplement.

The flavonoid quercetin is frequently found in low amounts as a secondary plant metabolite in fruits and vegetables. Isolated quercetin is also marketed as a dietary supplement, mostly as the free quercetin aglycone, and frequently in daily doses of up to 1000mgd-1 exceeding usual dietary intake levels. The present review is dedicated to safety aspects of isolated quercetin used as single compound in dietary supplements. Among the numerous published human intervention studies, adverse effects following supplemental quercetin intake have been rarely reported and any such effects were mild in nature. Published adequate scientific data for safety assessment in regard to the long-term use (>12 weeks) of high supplemental quercetin doses (≥1000mg) are currently not available. Based on animal studies involving oral quercetin application some possible critical safety aspects could be identified such as the potential of quercetin to enhance nephrotoxic effects in the predamaged kidney or to promote tumor development especially in estrogen-dependent cancer. Furthermore, animal and human studies with single time or short-term supplemental quercetin application revealed interactions between quercetin and certain drugs leading to altered drug bioavailability. Based on these results, some potential risk groups are discussed in the present review.

Uptake of quercetin reduces larval sensitivity to lambda-cyhalothrin in Helicoverpa armigera

Quercetin, one of the most abundant dietary flavonoids, is widely present in nature. In this study, the effects of quercetin ingestion on Helicoverpa armigera larvae growth and its sensitivity to lambda-cyhalothrin were assessed. The median lethal concentration (LC50) value of lambda-cyhalothrin to quercetin-fed H. armigera larvae was 2.39-fold higher than the control, suggesting a reduced sensitivity to lambda-cyhalothrin. Piperonyl butoxide (PBO) treatment effectively synergized lambda-cyhalothrin efficacy in quercetin-fed H. armigera larvae with a synergistic ratio of 2.36. Moreover, the growth of H. armigera larvae was inhibited by the quercetin uptake. To understand the reduced sensitivity to lambda-cyhalothrin, we measured the enzymatic activity of cytochrome P450 monooxygenases (P450s), as well as transcriptional responses of three P450s genes in quercetin-fed H. armigera larvae. We found that cytochrome P450 monooxygenases involved in the observed lambda-cyhalothrin tolerance in quercetin-fed H. armigera. After fed on quercetin for 48 h, 7-ethoxycoumarin-O-deethylase (ECOD) activity was significantly elevated in quercetin-fed H. armigera larvae; meanwhile, the expression level of CYP6B6, CYP6B8 and CYP321A1 was up-regulated. In conclusion, P450s played a crucial role in the metabolic adaptation of H. armigera larvae to its host plant’s secondary metabolites as well as synthetic insecticides. The reduced lambda-cyhalothrin sensitivity in quercetin-fed H. armigera larvae suggested that previous exposure to the host plant-derived quercetin is likely to compromise the efficacy of pyrethroid insecticides.