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Idiopathic pulmonary fibrosis is an agnogenic chronic disorder with high morbidity and low survival rate. Quercetin is a flavonoid found in a variety of herbs with anti-fibrosis function. In this study, bleomycin was employed to induce a pulmonary fibrosis mouse model. The quercetin administration ameliorated bleomycin-induced pulmonary fibrosis, evidenced by the expression level changes of hydroxyproline, fibronectin, [alpha]-smooth muscle actin, Collagen I, and Collagen III. Similar results were observed in transforming growth factor (TGF)-[beta]-treated human embryonic lung fibroblast (HELF). The bleomycin or TGF-[beta] administration caused the increase of sphingosine-1-phosphate (S1P) level in pulmonary tissue and HELF cells, as well as its activation-required kinase, sphingosine kinase 1 (SphK1), and its degradation enzyme, sphinogosine-1-phosphate lyase (S1PL). However, the increase of S1P, SphK1, and S1PL was attenuated by application of quercetin. In addition, the effect of quercetin on fibrosis was abolished by the ectopic expression of SphK1. The colocalization of SphK1/S1PL and fibroblast specific protein 1 (FSP1) suggested the roles of fibroblasts in pulmonary fibrosis. In summary, we demonstrated that quercetin ameliorated pulmonary fibrosis in vivo and in vitro by inhibiting SphK1/S1P signaling.Key words: bleomycin, pulmonary fibrosis, quercetin, sphingosine-1-phosphate, sphingosine kinase 1.La fibrose pulmonaire idiopathique est une maladie chronique agnogenique associee a une morbidite elevee et a de faibles taux de survie. La quercetine est un flavonoide trouve dans une variete d'herbes medicinales ayant une propriete anti-fibrogene. Dans cette etude, la bleomycine a ete utilisee pour induire une fibrose pulmonaire chez la souris. L'administration de quercetine ameliorait la fibrose pulmonaire induite par la bleomycine, comme le demontraient les changements des niveaux d'expression d'hydroxyproline, de fibronectine, d'[alpha]-actine du muscle lisse, de collagene I et de collagene III. Des resultats similaires ont ete observes chez des fibroblastes pulmonaires embryonnaires humains (FPEH) traites au facteur de croissance transformant-[beta] (TGF-[beta]). L'administration de bleomycine ou de TGF-[beta] provoquait un accroissement des niveaux de sphingosine-1-phosphate (S1P) dans le tissu pulmonaire et dans les FPEH, de meme que de la kinase qui l'active, la sphingosine-1-phosphate kinase 1 (SphK1), et son enzyme de degradation, le sphingosine-1-phosphate lyase (S1PL). Toutefois, l'accroissement de S1P, SphK1 et S1PL etait attenue par l'administration de quercetine. De plus, l'effet de la quercetine sur la fibrose etait aboli par l'expression ectopique de SphK1. La colocalisation de SphK1/ S1PL avec la proteine specifique du fibroblaste FSP1 suggerait que les fibroblastes avaient un role a jouer dans la fibrose pulmonaire. En resume, les auteurs ont demontre que la quercetine ameliorait la fibrose pulmonaire in vivo et in vitro en inhibant la signalisation par Sph1K/S1P. [Traduit par la Redaction]Mots-cles: bleomycine, fibrose pulmonaire, quercetine, sphingosine-1-phosphate, sphingosine kinase 1., IntroductionIdiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial pulmonary disorder that causes irreversible fibrosis (Le et al. 2014). The morbidity of IPF is 20/100 000 in males and 13/100 [...]

ABSTRACT Background: Plant secondary metabolites may induce adaptive cellular stress-responses in a variety of cells including neurons at the sub-toxic doses ingested by humans. Such 'neurohormesis' phenomenon, activated by flavonoids [...]

ABSTRACT Background: Influenza virus is still at large and seriously affects social welfare and health. Dianthus superbus is a well-known medicinal plant widely used in Mongolian and Chinese traditional medicine [...]

Quercetin (Que) is one of main compounds in Lysimachia christinae Hance (Christina loosestrife), and has both medicinal and nutritional value. Glycosides from Tripterygium wilfordii Hook.f. (lei gong teng [the thunder duke vine]; TG) have diverse and broad bioactivities but with a high incidence of liver injury. Our previous study reported on the hepatoprotective properties of an ethanol extract from L. christinae against TG-induced liver injury in mice. This research is designed to observe, for the first time, the possible protective properties of the compound Que against TG-induced liver injury, and the underlying mechanisms that are involved in oxidative stress and anti-inflammation. The results indicated that TG caused excessive elevation in serum levels of alanine/aspartate transaminase (ALT/AST), alkaline phosphatase (ALP), gamma glutamyl transferase (γ-GT), and proinflammatory cytokine tumor necrosis factor-alpha (TNF-α), as well as hepatic lipid peroxidation (all P < 0.01). On the other hand, following TG exposure, we observed significantly reduced levels of biomarkers, including hepatic glutathione (GSH), glutathione-S-transferase (GST), glutathione peroxidase (GPx), and the anti-inflammatory cytokine interleukin (IL)-10, as well as the enzyme activity and mRNA expression of copper- and zinc-containing superoxide dismutase (CuZn-SOD) and catalase (CAT) (all P < 0.01). Nevertheless, all of these alterations were reversed by the pre-administration of Que or the drug bifendate (positive control) for 7 consecutive days. Therefore, this study suggests that Que ameliorates TG-induced acute liver injury, probably through its ability to reduce oxidative stress and its anti-inflammatory properties. Key words: hepatoprotection, oxidative stress, antioxidant enzymes, pro-inflammatory cytokines, anti-inflammatory cytokines. La quercetine (Que), un des composes principaux de Lysimachia christinae Hance, possede des vertus medicinales et nutritionnelles. Les glycosides de Tripterygium spp. (GT) exercent des activites biologiques variees et etendues, mais leur utilisation s'accompagne d'une incidence elevee de dommage hepatique. Une etude precedente realisee par les auteurs a rapporte l'effet hepatoprotecteur d'un extrait a l'ethanol de L. christinae envers le dommage hepatique induit par les GT chez la souris. Cette recherche a ete concue afin d'examiner de maniere plus approfondie l'effet protecteur possible de la Que envers le dommage hepatique induit par les GT, et les mecanismes sous-jacents impliques dans les effets antioxydants and antiinflammatoires, pour la premiere fois. Les resultats ont indique que les GT provoquaient une elevation excessive d'alanine/ aspartate transaminase (ALT/AST), de phosphatase alcaline (PA) et de gamma-glutamyl transferase (γ-GT) seriques, de la peroxydation lipidique hepatique, et des niveaux du facteur necrosant des tumeurs-alpha (TNF-α), une cytokine pro-inflammatoire. Par contre, une reduction significative de biomarqueurs incluant le glutathion hepatique (GSH) et l'activite enzymatique et l'expression de l'ARNm de la glutathion-S-transferase (GST), la glutathion peroxydase (GPx), la superoxyde dismutase a cuivre et zinc (CuZn-SOD) et la catalase (CAT), de meme que la cytokine anti-inflammatoire interleukine-10, a ete observee a la suite d'une exposition aux GT (pour tous P < 0,01). Toutefois, toutes ces anomalies etaient renversees de maniere evidente par une administration prealable de Que et de bifendate pendant 7 jours consecutifs. En consequence, l'etude presente suggere que la Que peut ameliorer le dommage hepatique aigu induit par les GT, probablement par l'intermediaire d'une activite antioxydante et antiinflammatoire. [Traduit par la Redaction] Mots-cles : hepatoprotection, stress oxydant, enzymes antioxydantes, cytokines pro-inflammatoires, cytokines anti-inflammatoires., Introduction Drug-induced liver injury (DILI), as a rare but severe adverse drug reaction that represents a major problem in pharmacotherapy, both clinically and economically. Nowadays, DILI has been the major [...]

The pathogenesis of acute pancreatitis (AP) is still poorly understood. Thus, a reliable pharmacological therapy is currently lacking. In recent years, an impairment of the energy metabolism of pancreatic acinar cells, caused by [Ca.sup.2+]-mediated depolarization of the inner mitochondrial membrane and a decreased ATP supply, has been implicated as an important pathological event. In this study, we investigated whether quercetin exerts protection against mitochondrial dysfunction. Following treatment with or without quercetin, rat pancreatic acinar cells were stimulated with supramaximal cholecystokinin-8 (CCK). CCK caused a decrease in the mitochondrial membrane potential (MMP) and ATP concentration, whereas the mitochondrial dehydrogenase activity was significantly increased. Quercetin treatment before CCK application exerted no protection on MMP but increased ATP to a normal level, leading to a continuous decrease in the dehydrogenase activity. The protective effect of quercetin on mitochondrial function was accompanied by a reduction in CCK-induced changes to the cell membrane. Concerning the molecular mechanism underlying the protective effect of quercetin, an increased AMP/ATP ratio suggests that the AMP-activated protein kinase system may be activated. In addition, quercetin strongly inhibited CCK-induced trypsin activity. The results indicate that the use of quercetin may be a therapeutic strategy for reducing the severity of AP. Key words: acute pancreatitis, CCK-8, quercetin, trypsin inhibitor, mitochondrial dysfunction. La pathogenese de la pancreatite aigue (PA) est encore mal comprise. Consequemment, une therapie pharmacologique fiable fait actuellement defaut. Recemment, une defaillance du metabolisme des cellules pancreatiques acinaires, causee par une depolarisation de la membrane interne de la mitochondrie dependante du [Ca.sup.2+] et une diminution de l'apport en ATP, a ete identifiee comme evenement pathologique important. Dans l'etude presente, nous avons examine si la quercetine peut exercer une protection contre la dysfonction mitochondriale. A la suite d'un traitement avec ou sans quercetine, des cellules acinaires pancreatiques de rat ont ete stimulees avec une dose supra-maximale de cholecystokinine-8 (CCK). La CCK provoquait une diminution du potentiel membranaire mitochondrial (PMM) et de la concentration d'ATP, alors que l'activite deshydrogenase mitochondriale etait significativement accrue. Le traitement a la quercetine avant l'application de CCK n'exer^ait aucune protection sur le PMM mais augmentait l'ATP a un niveau normal, resultant en une diminution constante de l'activite deshydrogenase. L'effet protecteur de la quercetine sur la fonction mitochondriale etait accompagne d'une diminution des alterations de la membrane cellulaire induites par la CCK. En ce qui concerne le mecanisme moleculaire qui sous-tend l'effet protecteur de la quercetine, un accroissement du rapport AMP/ATP suggere que le systeme AMPK (AMP-activated protein kinase) puisse etre active. De plus, la quercetine inhibait fortement l'activite de la trypsine induite par la CCK. Les resultats indiquent que l'utilisation de quercetine pourrait constituer une strategie therapeutique permettant de reduire la severite de la PA. [Traduit par la Redaction] Mots-cles: pancreatite aigue, CCK-8, quercetine, inhibiteur de trypsine, dysfonction mitochondriale., Introduction Acute pancreatitis (AP), an inflammatory autodigestive disease of the exocrine pancreas, is characterized by premature intraacinar activation of digestive enzymes, secretory block, basolateral secretion, and disorganization of the cytoskeleton [...]

Problem statement: Demand for cognitive-enhancing drugs is growing. Numerous medicinal plants possessing antioxidant activity have received much attention as food supplement to improve cognitive function. Quercetin is a potent free radical scavenger and antioxidant. However, the limitations of quercetin: Rapidly metabolized is an obstacle to its use for a cognitive enhancer. In addition, the burden of blood brain barrier can be overcome by nasal administration and liposomes. In the present study, we investigated whether nasal administration of quercetin liposomes could improve spatial memory in healthy adult rats. Approach: Male Wistar rats were pretreated with quercetin liposomes, containing 0.5 mg of quercetin in 20 [micro]L (dose = 20 [micro]g), via right nasal cavity once daily continually for 4 weeks. Evaluation of rodent learning and memory was assessed by Morris water maze test and then all rats were sacrificed for determining the survival and cholinergic neurons densities in hippocampus. Results: Quercetin liposomes via nasal route treated rats exhibited a significant improvement in cognitive performance. In addition, nasal administration of quercetin liposomes also resulted in induced the densities of survival and cholinergic neurons in hippocampus. However, further researches about the precise underlying mechanism are still required. Conclusion: Our studies demonstrate that quercetin liposomes via nasal administration may have a candidate for cognitive enhancer in the future. Key words: Quercetin liposomes, nasal administration, antioxidant, blood brain barrier, cognitive enhancer, INTRODUCTION Memory is a complex process requiring the coordination of many different regions of brain and many neurotransmitter systems. Among the various neurotransmitter systems, the cholinergic system has attracted special [...]

Quercetin is a unique dietary polyphenol because it can exert biphasic dose-responses on cells depending on its concentration. Cancer preventative effects of quercetin are observed at concentrations of approximately 1-40 pM and are likely mediated by quercetin's antioxidant properties. Pro-oxidant effects are present at cellular concentrations of 40-100 [micro]M. However, at higher concentrations, many novel pathways in addition to ROS contribute to its effects. The potent bioactivity of quercetin has led to vigorous study of this compound and revealed numerous pathways that could interact synergistically to prevent or treat cancer. The effect of intake and concentration on emerging pathways and how they may interact are discussed in this review. Key words: estrogen receptor, HSPs, P53, quercetin, ROS doi: 10.1111/j.1753-4887.2010.00301.x

Problem statement: Recent findings demonstrated the crucial role of oxidative stress on the pathophysiology of Alzheimer's Disease (AD). Antioxidant intake is beneficial to delay or inhibit the progression of this disease. Quercetin, a bioflavonoid in fruits and vegetables, has a powerful antioxidant activity both in vitro and in vivo. Claims that quercetin has many biological activities. However, quercetin is rapidly metabolized and limited ability to cross the blood-brain-barrier are obstacles to its use for treatment of AD. Liposomes have been used as an effective delivery system to the brain. Advantages associated with the nasal administration over oral route include higher bioavailability due to no first pass hepatic metabolism and rapid absorption leading to shorter time to onset of effect. Based on this information, the effects of quercetin liposomes via nasal route on improving cognitive behavior and biochemical markers of oxidative stress, Superoxide Dismutase (SOD), catalase, glutathione and Malondialdehyde (MDA) in the hippocampus in animal model of AD were investigated. Approach: Male Wistar rats were pretreated with quercetin liposomes, containing 0.5 mg of quercetin in 20 [micro]L (dose = 20 [micro]g), via intranasal route once daily continually for 2 weeks before and 1 week after AF64A administration. Learning and memory was evaluated using the Morris water maze test at 7 days after the AF64A administration and then the rats were sacrificed for determining the content of MDA and the activities of SOD, catalase and glutathione in the hippocampus. Results: Quercetin liposomes via nasal administration significantly improved memory impairment by inhibiting the oxidative damage in hippocampus. The possible underlying mechanisms might be partly associated with the decrease the level of MDA whereas increase the activity of SOD, catalase and glutathione. Conclusion: Our studies demonstrated that quercetin liposomes via nasal administration may have a therapeutic importance in the clinical management of AD. Key words: Quercetin liposomes, nasal administration, spatial memory, oxidative stress, INTRODUCTION Reactive Oxygen Species (ROS), such as superoxide anion, hydroxyl radical and hydrogen peroxide, have a causal relationship with oxidative stress. Many studies have demonstrated that overproduction of ROS can [...]

Problem statement: At present, the prevalence of neuropsychological disorders particularly anxiety, depression and dementia are increase. Many strategies have been developed in order to increase the efficiency of treatment and decrease side effects. Oxidative stress has been reported to play an important role on various path physiological states. Quercetin is a flavonoid commonly found in fruits and vegetables. It has potent antioxidant effects in vivo and in vitro. However, poor absorption, rapid metabolism and limited ability to cross the blood-brain-barrier are obstacles to its use for treatment of neuropsychological disorders. Nasal administration has been proposed as a noninvasive method to deliver bioactive substances to the brain. This route of administration has the potential of decreased hepatic metabolism and greater access to the brain tissue through the olfactory nerve compared to the oral route and could be a potential method of delivering quercetin to the CNS. Approach: This study was set up to determine the effect of quercetin liposomes via nasal administration on the anti-anxiety, anti-depression like activity and cognitive enhancing effect. In this case, Male Wistar rats were administered quercetin liposomes, containing 0.5 mg of quercetin in 20 [micro]L (dose = 20 [micro]g), via intranasal route once daily continually for 4 weeks. The anxiolytic activity, anti-depression like activity and cognitive enhancing effect were determined after single administration, 1-4 week of treatment using elevated plus maze test, forced swimming test and Morris water maze test respectively. Results: Quercetin liposomal encapsulation via nasal route possessed anxiolytic, anti-depression like activity and cognitive enhancing effect at all treatment duration. Conclusion: Our results demonstrated the anxiolytic, anti-depression like-activity and cognitive enhancing effect of quercetin liposomes via nasal administration and suggested that it might be used as a novel therapeutic strategy for mood disorder and cognitive deficit condition. However, further investigations about precise underlying mechanism are still required. Key words: Quercetin liposomes, nasal administration, anxiety, anti-depression like activity, cognitive enhancing effect, INTRODUCTION At present, it has been reported that more than 450 million people worldwide suffer from the mental and brain disorders, particularly anxiety, depression and dementia (Indian Council of Medical [...]

Quercetin is a plant-derived bioflavonoid with potentially beneficial effects on the cardiovascular system. Studies focused on the efficiency of flavonoids against ischemia-reperfusion (I/R) injury have demonstrated that quercetin exerts robust protective effects in renal, cerebral, and hepatic I/R models. However, there is only limited evidence about the effect of quercetin on myocardial I/R injury. Therefore, the aim of the current study was to examine the effect of quercetin on isolated rat heart during ischemia and reperfusion. Rat hearts perfused according to Langendorff at 37 °C were examined during 25 min global ischemia followed by 120 min reperfusion. Quercetin (15 µmol/L) was administered either 15 min before ischemia (group Q1), or during the entire reperfusion period (group Q2). Changes in functional parameters of the hearts were measured during the initial 40 min of reperfusion. At the end of the experiment, the hearts were stained with tetrazolium to estimate the size of infarction (IS). Our study showed that quercetin improved postischemic recovery of functional parameters of isolated hearts in both treated groups. This improvement was manifested by significantly higher values of left ventricular developed pressure (LVDP) and the maximal rates of pressure development and fall (+[(dP/dt).sub.max] and -[(dP/dt).sub.max]) and by significantly lower increase of end-diastolic pressure. Coronary flow was not significantly changed during reperfusion in the group treated before ischemia, but was significantly increased in the group treated during reperfusion. Quercetin also significantly reduced IS in both groups, more markedly in postischemically treated group. We conclude that acute quercetin treatment exerts significant positive effects on isolated hearts during I/R injury. These results are consistent with the beneficial effects of quercetin and other flavonoids on the cardiovascular system. Key words: quercetin, ischemia-reperfusion, isolated heart. La quercetine est un bioflavonolde d'origine vegetale qui pourrait avoir des effets beeneefiques sur le systeme cardiovasculaire. Les etudes sur l'efficacite des flavonoldes contrelaleesion d'ischeemie-reperfusion (I/R) ont demontre que la querceetine a des effets protecteurs tres positifs dans les modeles d'I/R renaux, cerebraux et hepatiques. Toutefois, il existe peu de donneees probantes concernant l'effet de la quercetine sur la lesion d'I/R myocardique. Par consequent, la presente etude a eu pour but d'examiner l'effet de la quercetine sur le coeur isole; du ratdurantl'ischemie et la reperfusion. On a examinee des coeurs de rats, perfuseesselon la meethode de Langendorff, durant une ischemie globale de 25 min a 37 °C, suivie d'une reperfusion de 120 min. Ona administre la quercetine (15 µmol/L) soit 15 minutes avant l'ischeemie, (groupe Q1), soit durant toute la peeriode de reperfusion (groupe Q2). On a mesure les modifications des parameetres fonctionnels des coeurs au cours des 40 premieres minutes delareperfusion.A la fin de l'experience, on a colore les cours avec du tetrazolium pour eevaluer la taille de l'infarctus (TI). Notre etude a montre une ameliorationdureetablissement postichemique des parameetres fonctionnels dans les cours isoles des deux groupes traiteesa la querceetine. Cette amelioration s'est traduite par des valeurs significativement plus elevees de la PDVG, de la +[(dP/dt).sub.max] et de la -[(dP/dt).sub.max], et par une augmentation significativement plus faible de la pression teleediastolique. Le debit coronaire est demeuree assez stable durant la reperfusion chez le groupe traite avant l'ischemie, mais a significativement augmente chez le groupe traite durant la reperfusion. La querceetine a de plus diminue considerablement la TI dans les deux protocoles expeerimentaux, mais la diminution a eetee plus marqueechezlegroupe traite apresl'ischemie. Nous pouvons conclure qu'un traitement aigu a la querceetine a des effets positifs significatifs sur les cours isoles, durant une lesion d'I/R. Ces resultats sont en correlation avec d'autres effets benefiques de la quercetine et autres flavonoldes sur le systeme cardiovasculaire. Mots-cles: quercetine, ischeemie-reperfusion, coeur isole. [Traduit par la Redaction], Introduction Flavonoids are a large group of polyphenolic substances that are widely present in fruits, vegetables, red wine, tea, and other food plant sources. They have been reported to exert [...]

In the hepatopulmonary syndrome (HPS), a common complication of liver cirrhosis, pulmonary endothelial endothelin B (ETB) receptor overexpression, enhanced endothelial nitric oxide (NO) synthase (eNOS)-derived NO production, and increases in pulmonary inducible NO synthase (iNOS) and heme oxygenase (HO-1) are important factors in the development of vasodilatation. These changes may be influenced by redox-sensitive signaling pathways, including nuclear factor-[kappa]B (NF-[kappa]B). In this study, our aim was to evaluate the effects of the flavonoid antioxidant quercetin on the development of HPS in rats with common bile duct ligation (CBDL). Rats were divided into the following 4 groups: rats subjected to CBDL, Sham (rats subjected to simulated CBDL), quercetin-treated sham, and quercetin-treated CBDL. Quercetin (50 mg/kg) was administered for 2 wk starting on d 14 after surgery. Increased NO production, overexpression of iNOS, eNOS, HO-1, and ETB-receptor and activation of NF-KB were observed in lung of CBDL rats. Quercetin inhibited oxidative stress, NF-[kappa]B activation, and the expression of different pulmonary mediators involved in HPS. Quercetin also ameliorated liver injury and reduced the expression of hepatic endothelin-1 and HO-1 in untreated cirrhotic rats. Our findings suggest that quercetin administered after the onset of hepatic injury significantly ameliorates pulmonary complications in CBDL rats and that limitation of cirrhotic evolution contributes to this effect.

It has been reported that naturally occurring quercetin exerts hepatoprotective effects through heme oxygenase-I (HO-I) induction. However, the precise mechanism of how ethanol-associated liver damage is counteracted by quercetin-enhanced HO-1 metabolism still remains unclear. To further decipher the protective role of quercetin on ethanol-induced liver damage, we treated human hepatocytes with quercetin and various (end) products of the HO-1 pathway. Our data clearly showed that quercetin treatment attenuated ethanol-induced damage, whereas hemoglobin and zinc protoporphyrin 9 (ZnPP) abolished such effects. Iron-II aggravated ethanol toxicity and was only partially reduced by quercetin. In contrast, carbon monoxide (CO) dose dependently inhibited ethanol-induced cytochrome P450 2E1 (CYP 2E1) activity and hepatotoxicity but had no influence on CYP 2E1 protein expression. Similarly, hemoglobin dramatically stimulated CYP 2E1 activity but not the protein expression in quercetin- and ethanol-cotreated hepatocytes. ZnPP significantly promoted CYP 2E1 protein expression in the presence and absence of CO treatment but inhibited ethanol-induced CYP 2E1 activation following CO incubation in quercetin- and ethanol-cotreated hepatocytes. These results suggested that quercetin virtually attenuated ethanol-derived oxidative damage via HO-1 induction. Heine degradation and CO release may mediate the protective effects through inhibiting ethanol-induced CYP 2E1 synthesis and enzymatic activity, respectively. quercetin; CYP 2E1; heine oxygenase-1; carbon monoxide

Dietary fiavonoids provide various beneficial effects for our health. We investigated the promotive effects of quercetin and myricetin on the intestinal barrier function in human intestinal Caco-2 cell monolayers. Transepithelial electrical resistance (TER) across the monolayers increased rapidly during incubation with quercetin, peaking at 6 h. Lucifer yellow flux, a paracellular marker, was dose-dependently lower after quercetin and myricetin treatments, although quercetin exhibited a more potent effect. Immunoblot analysis of tight junction (T J) proteins revealed that zonnula occludens (ZO)-2, occludin, and claudin-1 were distributed to the actin cytoskeleton fraction by quercetin without increasing their respective whole-cell levels and this distribution was correlated with the increases in TER. The claudin-4 level was elevated by quercetin in both the cytoskeleton fraction and whole cells after 12 h. Confocal microscopy showed the assembly of claudin-1 and -4 at the TJ by quercetin. An inhibitor of protein kinase C8 (PKC[delta]), rottlerin, enhanced the barrier function with changes in the distribution and expression of TJ proteins in a manner very similar to that of quercetin. Phosphorylation of PKC[delta] indicating the enzymatic activity in the cells was decreased by quercetin after 1 h. In the kinase assay, quercetin exhibits direct inhibition of the PKC[delta] isoform. This study demonstrates that quercetin enhances the intestinal barrier function through the assembly of ZO-2, occludin, and claudin-1 by inhibiting PKC[delta] and the increase in claudin-4 expression has an additional role after 12 h.

Quercetin is one of a broad group of natural polyphenolic flavonoid substances that are being investigated for their widespread health benefits. These benefits have generally been ascribed to its combination of antioxidant and anti-inflammatory activity, but recent in vitro evidence suggests that improved mitochondrial biogenesis could play an important role. In addition, the in vivo effects of quercetin on mitochondrial biogenesis exercise tolerance are unknown. We examined the effects of 7 days of quercetin feedings in mice on markers of mitochondrial biogenesis in skeletal muscle and brain, and on endurance exercise tolerance. Mice were randomly assigned to one of the following three treatment groups: placebo, 12.5 mg/kg quercetin, or 25 mg/kg quercetin. Following 7 days of treatment, mice were killed, and soleus muscle and brain were analyzed for mRNA expression of peroxisome proliferator-activated receptor-[gamma] coactivator (PGC1-[alpha]) and sirtuin 1 (SIRT1), and mitochondrial DNA (mtDNA) and cytochrome c. Additional mice underwent a treadmill performance run to fatigue or were placed in voluntary activity wheel cages, and their voluntary activity (distance, time, and peak speed) was recorded. Quercetin increased mRNA expression of PGC-1[alpha] and SIRT1 (P < 0.05), mtDNA (P < 0.05) and cytochrome c concentration (P < 0.05). These changes in markers of mitochondrial biogenesis were associated with an increase in both maximal endurance capacity (P < 0.05) and voluntary wheel-running activity (P < 0.05). These benefits of querectin on fitness without exercise training may have important implications for enhancement of athletic and military performance and may also extend to prevention and/or treatment of chronic diseases. flavonoid; mitochondria; endurance capacity

The flavonoid quercetin suppresses cell proliferation and enhances apoptosis in vitro, in this study, we determined whether quercetin protects against colon cancer by regulating the protein level of phosphatidylinositol 3-kinase (PI 3-kinase) and Akt or by suppressing the expression of proinflammatory mediators [cyclooxygenase (COX)-1, COX-2, inducible nitric oxide synthase (iNOS)] during the aberrant crypt (AC) stage. Forty male rats were randomly assigned to receive diets containing quercetin (0 or 4.5 g/kg) and injected subcutaneously with saline or azoxymethane (AOM; 2 times during wk 3 and 4). The colon was resected 4 wk after the last AOM injection and samples were used to determine high multiplicity AC foci (HMACF; foci with >4 AC) number, colonocyte proliferation and apoptosis by immunohistochemistry, expression of PI 3-kinase (p85 and p85[alpha] subunits) and Akt by immunoblotting, and COX-1, COX-2, and iNOS expression by real time RT-PCR. Quercetin-fed rats had fewer (P = 0.033) HMACF. Relative to the control diet, quercetin lowered the proliferative index (P = 0.035) regardless of treatment and diminished the AOM-induced elevation in crypt column cell number (P = 0.044) and expansion of the proliferative zone (P = 0.021). The proportion of apoptotic colonocytes in AOM- injected rats increased with quercetin treatment (P = 0.014). Levels of p85 and p85[alpha] subunits of PI 3-kinase and total Akt were unaffected by dietary quercetin. However, quercetin tended to suppress (P < 0.06) the expression of COX-1 and COX-2. Expression of iNOS was elevated by AOM injection (P = 0.0001). In conclusion, quercetin suppresses the formation of early preneoplastic lesions in colon carcinogenesis, which occurred in concert with reductions in proliferation and increases in apoptosis. It is possible the effects on proliferation and apoptosis resulted from the tendency for quercetin to suppress the expression of proinflammatory mediators.

Our aim was to investigate the effects of an oral supplementation of quercetin at 3 different doses on plasma concentrations of quercetin, parameters of oxidant/antioxidant status, inflammation, and metabolism. To this end, 35 healthy volunteers were randomly assigned to take 50, 100, or 150 mg/d (group Q50-Q150) quercetin for 2 wk. Fasting blood samples were collected at the beginning and end of the supplementation period. Compared with baseline, quercetin supplementation significantly increased plasma concentrations of quercetin by 178% (Q50), 359% (Q100), and 570% (Q150; P < 0.01 for all). High interindividual variation was found for plasma quercetin concentrations (36-57%). Quercetin did not affect concentrations of serum uric acid or plasma [alpha]- and [gamma]-tocopherols, oxidized LDL, and tumor necrosis factor-[alpha], or plasma antioxidative capacity as assessed by the ferric-reducing antioxidant potential and oxygen radical absorbance capacity assays. In addition, serum lipids and lipoproteins, body composition, and resting energy expenditure did not significantly change during quercetin supplementation. Pharmacokinetics of quercetin were investigated in a subgroup of 15 volunteers. The areas under the plasma concentration-time curves ranged from 76.1 [micro]mol x min x [L.sup.-1] to 305.8 [micro]mol x min x [L.sup.-1] (50- and 150-mg dosages, respectively). Median maximum plasma concentrations of quercetin (431 nmol/L) were observed 360 min after intake of 150 mg quercetin. In conclusion, daily supplementation of healthy humans with graded concentrations of quercetin for 2 wk dose-dependently increased plasma quercetin concentrations but did not affect antioxidant status, oxidized LDL, inflammation, or metabolism.

Exercise stress is associated with increased risk for upper respiratory tract infection. We have shown that exercise stress can increase susceptibility to infection. Quercetin, a flavonoid present in a wide variety of fruits and vegetables, has been reported to inhibit infectivity and replication of a broad spectrum of viruses and may offset the increase in susceptibility to infection associated with stressful exercise. This study examined the effects of quercetin feedings on susceptibility to the influenza virus A/Puerto Rico/8/34 (H1N1) following stressful exercise. Mice were randomly assigned to one of four treatment groups: exercise-placebo, exercise-quercetin, control-placebo, or control-quercetin. Exercise consisted of a run to fatigue (~140 min) on a treadmill for 3 consecutive days. Quercetin (12.5 mg/kg) was administered via gavage for 7 days before viral challenge. At 30 min after the last bout of exercise or rest, mice (n = 23-30) were intranasally inoculated with a standardized dose of influenza virus (0.04 hemagglutinating units). Mice were monitored daily for morbidity (time to sickness), symptom severity, and mortality (time to death) for 21 days. Exercise stress was associated with an increased susceptibility to infection [morbidity, mortality, and symptom severity on days 5-7 (P < 0.05)]; quercetin offset the increase in susceptibility to infection [morbidity, mortality, and symptom severity on days 5-7 (P < 0.05)] that was associated with stressful exercise. These data suggest that short-term quercetin feedings may prove to be an effective strategy to lessen the impact of stressful exercise on susceptibility to respiratory infection. nutrition; mice; infection; stress; virus

Quercetin is the most abundant flavonoid and is assumed to have positive effects on the gastrointestinal mucosa after dietary intake. The aim of the study was to analyze the influence of quercetin on intestinal barrier function using the human colonic epithelial cell line Caco-2. Transepithelial resistance (Rt), tracer fluxes of [[sup.3]H]-mannitol, [sup.22][Na.sup.+], and [sup.36][Cl.sup.-] as well as electrogenic ion transport were determined in Ussing chambers. Expression of tight junction (T J) proteins and mRNA was analyzed in Western blots and quantitative RT-PCR, respectively. Regulation of transcription was analyzed by reporter gene assay. Cellular distribution of TJ proteins was examined by confocal laser scanning microscopy (LSM). Apoptotic rate was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. Quercetin induced a dose-dependent increase of [R.sup.t] persisting for >2 d. Daily addition of quercetin was able to perpetuate the effect, which was seen whether quercetin was added apically or to the basolateral compartment. Parallel to the [R.sup.t] increase, quercetin induced a strong increase of the TJ protein claudin-4 but not of other claudins. Confocal LSM showed a localization of claudin-4 in TJ. Apoptotic rate was not affected by quercetin. Consistent with these changes, fluxes of [Na.sup.+] and [Cl.sup.-], but not of mannitol, were reduced. Reporter gene assays revealed a stimulatory effect of quercetin on claudin-4 transcription. The flavonoid quercetin enhances barrier function via transcriptional expression regulation of the TJ protein claudin-4, which represents an important protective effect of this food component against barrier disturbance in intestinal inflammation.

The lipophilic character of quercetin suggests that it can cross enterocyte membranes via simple diffusion. Therefore, it should be more bioavailable than its glucosides, which require preliminary hydrolysis or active transport for absorption. However, the published human studies show that quercetin is less bioavailable than its glucosides. Assuming that low bioavailability of quercetin aglycone provided to humans as a pure substance is the result of its low solubility in the digestive tract, we studied its bioavailability from dietary sources in which quercetin was dispersed in the food matrix, in a randomized crossover study, 9 volunteers took a single dose of either shallot flesh (99.2% quercetin glucosides and 0.8% quercetin aglycone) or dry shallot skin (83.3% quercetin aglycone and 16.7 % quercetin glucosides), providing 1.4 mg quercetin per kg of body weight. Blood samples were collected before and after consumption of shallot preparations. Plasma quercetin was measured on HPLC with electrochemical detection after plasma enzymatic treatment. The maximum plasma quercetin concentration of 1.02 [+ or -] 0.13[micro]mol/L was reached at 2.33 [+ or -] 0.50 h after shallot flesh consumption compared with 3.95 [+ or -] 0.62[micro]mol/L at 2.78 [+ or -] 0.15 h after dry skin consumption. The area under the concentration-time curve after dry skin consumption was 47.23 [+ or -] 7.53[micro]mol * [h.sup.-1] * [L.sup.-1] and was significantly higher than that after shallot flesh intake (22.23 [+ or -] 2.32 [micro]mol * [h.sup.-1] * [L.sup.-1]. When provided along with dietary sources, quercetin aglycone is more bioavailable than its glucosides in humans. Results point to the food matrix as a key factor.

Despite extensive studies, the fundamental mechanisms responsible for the development and progression of cardiovascular diseases have not yet been fully elucidated. Recent experimental and clinical studies have suggested that reactive oxygen species play a major pathological role. Oxidative stress reduction induced by flavonoids has been regarded by many as the most likely mechanism in the protective effects of these compounds; however, there is an emerging view that flavonoids may also exert modulatory actions on protein kinase and lipid kinase signaling pathways. Quercetin, a major flavonoid present in the human diet, has been widely studied, and its biological properties are consistent with its protective role in the cardiovascular system. However, it remains unknown whether the cardioprotective effects of quercetin may also occur through the modulation of genes involved in cell survival. The main goal of this study was to examine the gene expression profiling of cultured rat primary cardiomyocytes treated with quercetin using DNA microarrays and to relate these data to functional effects. Results showed distinct temporal changes in gene expression induced by quercetin and a strong upregulation of phase 2 enzymes, highlighting quercetin ability to act also with an indirect antioxidant mechanism. flavonoids; phase 2 enzymes; oxidative stress

Promising experimental studies suggest that quercetin has potential anti-inflammatory effects. However, the results of current clinical trials on quercetin's effects on the C-reactive protein (CRP), a sensitive inflammatory biomarker, are ambiguous. We conducted a meta-analysis of available randomized controlled trials (RCTs) to resolve this inconsistency and quantify the net effect of quercetin on circulating CRP concentrations. A systematic search was performed in several databases including SCOPUS, PubMed-Medline and Google Scholar until 16 June 2016. We used a random-effects model in combination with weight mean difference (WMD) and 95% confidence intervals (CI) for data analysis. Standard methods were used for the assessment of heterogeneity, meta-regression, sensitivity analysis and publication bias. The meta-analysis of seven RCTs (10 treatment arms) showed a significant reduction of circulating CRP levels (WMD: -0.33 mg/l; 95% CI: -0.50 to -0.15; P [less than] 0.001) following quercetin supplementation. In the subgroup analysis, a significant reducing effect was observed in trials with [succeeds/equal to]500 mg/day dosage (WMD: -0.34 mg/l; 95% CI: -0.52, -0.16; P[precedes/equal to]0.001) and in those with CRP [less than] 3 mg/l (WMD: -0.34 mg/l; 95% CI: -0.51, -0.18; P[precedes/equal to]0.001). In meta-regression, there was no association between changes in CRP concentrations, dose of supplementation and CRP baseline values. Our findings showed a significant effect of quercetin supplementation on the C-reactive protein--especially at doses above 500 mg/day and in patients with CRP [less than] 3 mg/l. European Journal of Clinical Nutrition (2017) 71, 1033-1039; doi: 10.1038/ejcn.2017.55; published online 24 May 2017, Author(s): M Mohammadi-Sartang [1]; Z Mazloom [1]; S Sherafatmanesh [1]; M Ghorbani [2]; Donya Firoozi [1] Introduction With more than 6000 identified compounds, flavonoids are structurally categorized into a variety [...]

Byline: Laxmi. Pattanashetti, Ashok. Taranalli, Vinay. Parvatrao, Rohit. Malabade, Dushyant. Kumar Objective: The objective of this study was to evaluate the neuroprotective effect of quercetin with donepezil in scopolamine-induced amnesia [...]

Epidemiological studies report that quercetin, an antioxidant flavonol found in apples, berries, and onions, is associated with reduced risk of coronary heart disease and stroke. Quercetin supplementation also reduces blood pressure in hypertensive rodents. The efficacy of quercetin supplementation to lower blood pressure in hypertensive humans has never been evaluated. We tested the hypothesis that quercetin supplementation reduces blood pressure in hypertensive patients. We then determined whether the antihypertensive effect of quercetin is associated with reductions in systemic oxidant stress. Men and women with prehypertension (n = 19) and stage 1 hypertension (n = 22) were enrolled in a randomized, double-blind, placebo-controlled, crossover study to test the efficacy of 730 mg quercetin/d for 28 d vs. placebo. Blood pressure (mm Hg, systolic/diastolic) at enrollment was 137 [+ or -] 2/86 [+ or -] 1 in prehypertensives and 148 [+ or -] 2/96 [+ or -] 1 in stage 1 hypertensive subjects. Blood pressure was not altered in prehypertensive patients after quercetin supplementation. In contrast, reductions in (P < 0.01) systolic (-7 [+ or -] 2 mm Hg), diastolic (-5 [+ or -] 2 mm Hg), and mean arterial pressures (-5 [+ or -] 2 mm Hg) were observed in stage 1 hypertensive patients after quercetin treatment. However, indices of oxidant stress measured in the plasma and urine were not affected by quercetin. These data are the first to our knowledge to show that quercetin supplementation reduces blood pressure in hypertensive subjects. Contrary to animal-based studies, there was no quercetin-evoked reduction in systemic markers of oxidative stress.

The dietary flavonoid quercetin reduces blood pressure and improves endothelial function in several rat models of hypertension. We analyzed the effects of quercetin and its methylated metabolite isorhamnetin on the aortic endothelial dysfunction induced by incubation with angiotensin II (Angll) in vitro for 6 h. Angll diminished the relaxant responses to acetylcholine in phenylephrine-contracted aorta. Coincubation with quercetin or isorhamnetin, or addition of superoxide ([0.sub.2]-) dismutase or apocynin to the assay medium, prevented these inhibitory effects. At 6 h, Angll induced a marked increase in [0.sub.2]- production as measured by dihydroethidium fluorescence, which was prevented by quercetin and isorhamnetin. Angll also increased the expression of p[47.sup.phox], a regulatory subunit of the membrane NADPH oxidase. Immunohistochemical analysis revealed that overexpression of p[47.sup.phox] occurred mainly in the medial layer, p[47.sup.phox] overexpression was also prevented by quercetin and isorhamnetin. Taken together, these results show for the first time, to our knowledge, that quercetin and isorhamnetin prevent Angll-induced endothelial dysfunction by inhibiting the overexpression of p[47.sup.phox] and the subsequent increased [0.sub.2]- production, resulting in increased nitric oxide bioavailability. J. Nutr. 137: 910-915, 2007.