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Atherosclerosis (AS) with iron and lipid overload and systemic inflammation is a risk factor for Alzheimer's disease. M1 macrophage/microglia participate in neuronal pyroptosis and recently have been reported to be the ferroptosis-resistant phenotype. Quercetin plays a prominent role in preventing and treating neuroinflammation, but the protective mechanism against neurodegeneration caused by iron deposition is poorly understood. ApoE -/- mice were fed a high-fat diet with or without quercetin treatment. The Morris water maze and novel object recognition tests were conducted to assess spatial learning and memory, and nonspatial recognition memory, respectively. Prussian blue and immunofluorescence staining were performed to assess the iron levels in the whole brain and in microglia, microglia polarization, and the degree of microglia/neuron ferroptosis. In vitro, we further explored the molecular biological alterations associated with microglial polarization, neuronal pyroptosis, and ferroptosis via Western blot, flow cytometry, CCK8, LDH, propidium iodide, and coculture system. We found that quercetin improved brain lesions and spatial learning and memory in AS mice. Iron deposition in the whole brain or microglia was reversed by the quercetin treatment. In the AS group, the colocalization of iNOS with Iba1 was increased, which was reversed by quercetin. However, the colocalization of iNOS with PTGS2/TfR was not increased in the AS group, suggesting a character resisting ferroptosis. Quercetin induced the expression of Arg-1 and decreased the colocalizations of Arg-1 with PTGS2/TfR. In vitro, ox-LDL combined with ferric ammonium citrate treatment (OF) significantly shifted the microglial M1/M2 phenotype balance and increased the levels of free iron, ROS, and lipid peroxides, which was reversed by quercetin. M1 phenotype induced by OF caused neuronal pyroptosis and was promoted to ferroptosis by L-NIL treatment, which contributed to neuronal ferroptosis as well. However, quercetin induced the M1 to M2 phenotype and inhibited M2 macrophages/microglia and neuron pyroptosis or ferroptosis. In summary, quercetin alleviated neuroinflammation by inducing the M1 to M2 phenotype to inhibit neuronal pyroptosis and protected neurons from ferroptosis, which may provide a new idea for neuroinflammation prevention and treatment.

Emerging evidence supports the beneficial effect of quercetin on liver mitochondrial disorders. However, the molecular mechanism by which quercetin protects mitochondria is limited, especially in alcoholic liver disease. In this study, C57BL/6N mice were fed with Lieber De Carli liquid diet (28% ethanol-derived calories) for 12 weeks plus a single binge ethanol and intervened with quercetin (100 mg/kg.bw). Moreover, HepG2 CYP2E1+/+ were stimulated with ethanol (100 mM) and quercetin (50 µM) to investigate the effects of mitochondrial protein frataxin. The results indicated that quercetin alleviated alcohol-induced histopathological changes and mitochondrial functional disorders in mice livers. Consistent with increased PINK1, Parkin, Bnip3 and LC3II as well as decreased p62, TOM20 and VDAC1 expression, the inhibition of mitophagy by ethanol was blocked by quercetin. Additionally, quercetin improved the imbalance of iron metabolism-related proteins expression in alcohol-fed mice livers. Compared with ethanol-treated Lv-empty HepG2 CYP2E1+/+ cells, frataxin deficiency further exacerbated the inhibition of mitochondrial function. Conversely, restoration of frataxin expression ameliorated the effect of ethanol. Furthermore, frataxin deficiency reduced the protective effects of quercetin on mitochondria disordered by ethanol. Attentively, ferric ammonium citrate (FAC) and deferiprone decreased or increased frataxin expression in HepG2 CYP2E1+/+ , respectively. Notably, we further found FAC reversed the increasing effect of quercetin on frataxin expression. Ultimately, silencing NCOA4 attenuated the inhibition of quercetin on LDH release and mitochondrial membrane potential increase, and similar results were observed by adding FAC. Collectively, these findings demonstrated quercetin increased frataxin expression through regulating iron level, thereby mitigating ethanol-induced mitochondrial dysfunction., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Quercetin, a polyphenol widely present in the plant kingdom, has received great interest due to pleiotropic effects. As evidenced by animal and cellular studies, quercetin exerts hepatoprotection against non-alcoholic fatty liver disease (NAFLD), particularly in hepatic steatosis and hepatitis. Mechanically, various hypotheses of such protective effects have been actively proposed, including improving fatty acid metabolism, anti-inflammation, anti-oxidant, modulating gut microbiota and bile acid, etc. Here, the role of quercetin in NAFLD was summarized. With a particular focus on molecular mechanism, we comprehensively discussed the pathways of quercetin on NAFLD based on the analysis from Gene Expression Omnibus (GEO) database and experimental evidence., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Scope: Atherosclerosis is the underlying pathogenesis of cardiovascular events caused by inflammation, and dietary intervention has been recommended as one fundamental prevention strategy. Herein, the anti-arteriosclerotic properties of quercetin are investigated by modulating galectin-3 (Gal-3)-NLR family, pyrin domain-containing 3 (NLRP3) pathway., Methods and Results: Plaques from ApoE -/- mice fed by high-fat diet (HFD) with or without quercetin (100 mg (kg·bw) -1 ) for 16 weeks, and carotid plaques from patients with carotid stenosis are collected for histopathological examinations and molecular mechanism assays. Quercetin significantly alleviates atherosclerotic lesions and reduces lipid retention caused by HFD. Proteomic technology identified Gal--3 increased by HFD but lowered by quercetin. Furthermore, immunofluorescence and immunohistochemistry exhibit higher expressions of Gal-3 and NLRP3 in carotid plaques and plaques from HFD-fed mice, which are concurrently down-regulated by quercetin. Similar to TD139, quercetin dramatically suppresses NLRP3 inflammasome activation in oxidized low-density lipoprotein-laden macrophages, and accordingly alleviates cellular steatosis and IL-1β secretion, which is abolished by recombinant Gal-3. Co-immunoprecipitation shows Gal-3 binding to NLRP3 promotes inflammasome activation., Conclusion: Gal-3 initiates inflammatory lesions by activating NLRP3 inflammasome which functions as a candidate target of quercetin exerting favorable anti-atherogenic effects. The findings highlight a promising strategy for atherosclerosis prevention and treatment by naturally-occurring quercetin., (© 2021 Wiley-VCH GmbH.)

(1) Background: Pancreatic iron deposition has been found in the progression of type 2 diabetes (T2DM); however, whether ferroptosis contributes to the dysfunction of pancreatic β cells (PBC) remains enigmatic. Moreover, the potential protective effect of quercetin is also elusive; (2) Methods: T2DM mice model was established by multiple low dose streptozocin (STZ) injection, after which quercetin was intervened for 4 months; (3) Results: Substantially normalized glucose tolerance, diabetic symptoms, homeostasis model assessment for insulin resistance (HOMA-IR), and homeostasis model assessment for β cell (HOMA-β) index in comparison with the findings of T2DM control. Distorted pancreatic islets and especially shrunken mitochondria with cristae loss in PBC were observed in T2DM mice, which was ameliorated by quercetin. Meanwhile, quercetin lowered the iron level particularly in the islet in T2DM mice. In spite of compensatory xCT up-regulation, T2DM molding depleted glutathione (GSH), down-regulated glutathione peroxidase 4 (GPX4), and induced oxidative stress in pancreatic tissue, which was abolished partially by quercetin. More importantly, insulin secretion was worsened by ferroptosis-inducing erastin or RAS-selective lethal compounds 3 (RSL-3). Quercetin, ferroptosis inhibitor ferrostatin-1 and iron-chelating deferoxamine, rescued cell viability when cells were challenged with high-glucose; (4) Conclusions: Our findings identify that ferroptosis contributes to the PBC loss and dysfunction. Quercetin exerts beneficial effects on T2DM potentially by inhibiting pancreatic iron deposition and PBC ferroptosis, highlighting promising control strategies of T2DM by quercetin.

Background: Emerging evidence has supported that intensive exercise induces weakened performance and immune and metabolic disorders. We systematically evaluated the effects of quercetin against hepatic inflammatory damage caused by repeated intensive exercise and explored the potential mechanism., Methods: Male BALB/c mice were administered quercetin (100 mg/kg BW) for four weeks, and performed a treadmill running protocol of 28 m/min, 5° slope, 90 min/day concurrently for the last seven days., Results: Quercetin administration reduced the leakage of aspartic acid and alanine aminotransferase and improved ultrastructural abnormalities such as swelling, and degeneration caused by high-intensity running in mice. Quercetin significantly decreased the hepatic and plasmatic levels of inflammatory cytokines IL-1β, IL-6, TNF-α, inducible nitric oxide synthase, cyclooxygenase-2 and intercellular adhesion molecule-1-provoked by over-exercise. Furthermore, diminished activation and nuclear translocation of NF-κB were found after quercetin treatment through inhibiting IKKα and Iκbα phosphorylation of intensive running mice., Conclusion: Quercetin offers protection for mouse livers against intensive sports-induced inflammatory injury, and the suppression of the NF-κB signal transduction pathway may play a role in its anti-inflammatory effects. Our findings broaden our understanding of natural phytochemicals as a promising strategy to prevent excessive exercise damage.

Scope: Naturally occurring quercetin has been found to induce mitophagy and prevent nonalcoholic fatty liver disease (NAFLD). However, it still remains elusive whether frataxin upregulation by quercetin contributes to the beneficial effect through mitophagy or not., Methods and Results: Adult male C57BL/J mice were fed a high-fat diet (HFD, 60% of energy from fat) with quercetin (100 mg kg -1 body weight) or not for 10 weeks. Quercetin alleviated HFD-induced histopathological changes, disorders of lipid metabolism, and mitochondrial damage. Moreover, quercetin blocked mitophagy suppression by HFD based on the increased LC3II, PTEN-induced putative kinase 1 (PINK1) and Beclin1 expressions, as well as decreased p62 levels. Quercetin also improved the Parkin translocation to mitochondria confirmed by immunofluorescence. Specifically, frataxin was lowered in the liver of HFD-fed mice or HepG2 cell incubated with oleate/palmitate but restored by quercetin, and quercetin's regulation of frataxin may depend on p53. Furthermore, lentivirus-mediated stable knockdown of frataxin in HepG2 inhibited PINK1-Parkin-associated mitophagy and resulted in lipid accumulation. Frataxin was further decreased by free fatty acids in knockdown cells concomitantly with depressed PINK1-Parkin-associated mitophagy, which was partially normalized by quercetin., Conclusion: Quercetin alleviated hepatic steatosis by enhancing frataxin-mediated PINK1/Parkin-dependent mitophagy, highlighting a promising preventive strategy and mechanism for NAFLD by quercetin., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Iron is a life-supporting micronutrient that is required in the human diet, and is essential for maintaining physiological homeostasis. Properly harnessing a redox-active metal such as iron is a great challenge for cells and organisms because an excess of highly reactive iron catalyzes the formation of reactive oxygen species and can lead to cell and tissue damage. Quercetin is a typical flavonoid that is commonly found in fruits and vegetables and has versatile biological effects. From a classical viewpoint, owing to its unique chemical characteristics, quercetin has long been associated with iron metabolism only in the context of its iron-chelating and ROS-scavenging activities. However, within the field of human iron biology, expanding concepts of the roles of quercetin are flourishing, and great strides are being made in understanding the interactions between quercetin and iron. This progress highlights the varied roles of quercetin in iron metabolism, which involve much more than iron chelation alone. A review of these studies provides an ideal context to summarize recent progress and discuss compelling evidence for therapeutic opportunities that could arise from a better understanding of the underlying mechanisms., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Scope: Increased iron deposition in the myocardium in alcoholics may lead to increased risk of cardiac dysfunction. Quercetin has been demonstrated to quench production of intracellular free iron-induced -OH, but the effect of quercetin in ethanol-induced cardiac damage remains unclear. This study aims to explore whether quercetin attenuates ethanol-induced iron uptake and myocardial injury by regulating angiotensin II-L-type voltage-dependent Ca2+ channel (Ang II-LTCC)., Methods and Results: Adult male C57BL/6J mice are isocalorically pair-fed either a regular or ethanol-containing Lieber De Carli liquid diets supplemented with either quercetin (100 mg kg -1  bw) or desferrioxamine mesylate (DFO, 100 mg kg -1 bw) for 15 weeks. Quercetin alleviated ethanol-induced histopathological changes, creatine kinase isoenzyme release, Ang II secretion, ROS generation, total cardiac iron, and labile iron level. Ethanol exposure or quercetin intervention fails to regulate traditional iron transporters except LTCC. LTCC is upregulated by ethanol and inhibited by quercetin. In H9C2 cell, LTCC is increased by ethanol (100 mm) and/or Ang II (1 μm) concomitant with iron disorders and oxidative stress. This effect is partially normalized by quercetin (50 μm), nifedipine (LTCC inhibitor, 15 μm), or losartan (Ang II receptor antagonist, 100 μm)., Conclusion: Alcohol-induced cardiac injury is associated with excessive NTBI uptake mediated by Ang II-LTCC activation which may be mediated by quercetin against ethanol cardiotoxicity., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Reactive oxygen species (ROS) have emerged as important molecules in cardiovascular function. Nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase is the major source of ROS in phagocytic and vascular cells. Several lines of evidence indicate that quercetin contributes to protecting against atherosclerosis. Herein, we investigated the effect of quercetin on alleviating atherosclerosis by regulating NADPH oxidase subunits expression in vivo, and explored the mechanism of quercetin suppressing the ROS overproduction stimulated by ox-LDL in mouse peritoneal macrophages (MPMs). Model ApoE KO mice were fed with either a normal chow diet or a high fat diet (HFD) supplemented with or without dosed quercetin for 24 weeks. Quercetin significantly reduced the atherosclerotic plaque area, alleviated the systemic oxidative stress, and suppressed aortic p47phox, p67phox expressions but partially reversed the NOX4 expression as compared to those in the HFD group. In vitro, quercetin effectively inhibited the ox-LDL induced ROS formation in MPMs, and blocked the vital step in activation of NADPH oxidase - membrane translocation of p47phox. Our findings suggest that regular consumption of dietary quercetin plays a role in preventing atherosclerosis giving its evident regulatory effect on subunits of NADPH oxidase., (Copyright © 2017. Published by Elsevier Ltd.)

Emerging evidence suggested mitophagy activation mitigates ethanol-induced liver injury. However, the effect of ethanol on mitophagy is inconsistent. Importantly, the understanding of mitophagy status after chronic ethanol consumption is limited. This study evaluated the effect of quercetin, a naturally-occurring flavonoid, on chronic ethanol-induced mitochondrial damage focused on mitophagy. An ethanol regime to mice for 15 weeks (accounting for 30% of total calories) led to significant mitochondrial damage as evidenced by changes of the mitochondrial ultrastructure, loss of mitochondrial membrane potential and remodeling of membrane lipid composition, which was greatly attenuated by quercetin (100 mg/kg.bw). Moreover, quercetin blocked chronic ethanol-induced mitophagy suppression as denoted by mitophagosomes-lysosome fusion and mitophagy-related regulator elements, including LC3II, Parkin, p62 and voltage-dependent anion channel 1 (VDAC1), paralleling with increased FoxO3a nuclear translocation. AMP-activated protein kinase (AMPK) and extracellular signal regulated kinase 2 (ERK2), instead of AKT and Sirtuin 1, were involved in quercetin-mediated mitophagy activation. Quercetin alleviated ethanol-elicited mitochondrial damage through enhancing mitophagy, highlighting a promising preventive strategy for alcoholic liver disease.

Iron, in its free ferrous states, can catalyze Fenton reaction to produce OH∙, which is recognized as a crucial role in the pathogenesis of alcoholic liver diseases (ALD). As a result of continuous decomposition of iron-containing compounds, lysosomes contain a pool of redox-active iron. To investigate the important role of intralysosomal iron in alcoholic liver injury and the potential protection of quercetin, male C57BL/6J mice fed by Lieber De Carli diets containing ethanol (30% of total calories) were cotreated by quercetin or deferoxamine (DFO) for 15 weeks and ethanol-incubated mice primary hepatocytes were pretreated with FeCl3, DFO, and bafilomycin A1 at their optimal concentrations and exposure times. Chronic ethanol consumption caused an evident increase in lysosomal redox-active iron accompanying sustained oxidative damage. Iron-mediated ROS could trigger lysosomal membrane permeabilization (LMP) and subsequent mitochondria apoptosis. The hepatotoxicity was attenuated by reducing lysosomal iron while being exacerbated by escalating lysosomal iron. Quercetin substantially alleviated the alcoholic liver oxidative damage and apoptosis by decreasing lysosome iron and ameliorating iron-mediated LMP, which provided a new prospective of the use of quercetin against ALD.

The mechanisms underlying intense exercise-induced liver damage and its potential treatments remain unclear. We explored the hepatoprotection and mechanisms of quercetin, a naturally occurring flavonoid, in strenuous exercise-derived endoplasmic reticulum stress (ERS) and inflammation. Intense exercise (28 m/min at a 5° slope for 90 min) resulted in the leakage of aminotransferases in the BALB/C mice. The hepatic ultrastructural malformations and oxidative stress levels were attenuated by quercetin (100 mg/kg·bw). Intense exercise and thapsigargin- (Tg-) induced ERS (glucose-regulated protein 78, GRP78) and inflammatory cytokines levels (IL-6 and TNF-α) were decreased with quercetin. Furthermore, quercetin resulted in phosphoinositide 3-kinase (PI3K) induction, Ca(2+) restoration, and blockade of the activities of Jun N-terminal kinase (JNK), activating transcription factor 6 (ATF6) and especially NF-κB (p65 and p50 nuclear translocation). A PI3K inhibitor abrogated the protection of quercetin on ERS and inflammation of mouse hepatocytes. SP600125 (JNK inhibitor), AEBSF (ATF6 inhibitor), and especially PDTC (NF-κB inhibitor) enhanced the quercetin-induced protection against Tg stimulation. Collectively, intense exercise-induced ERS and inflammation were attenuated by quercetin. PI3K/Akt activation and JNK, ATF6, and especially NF-κB suppression were involved in the protection. Our results highlight a novel preventive strategy for treating ERS and inflammation-mediated liver damage induced by intense exercise using natural phytochemicals.

Emerging evidence has demonstrated that chronic ethanol exposure induces iron overload, enhancing ethanol-mediated liver damage. The purpose of this study was to explore the effects of the naturally occurring compound quercetin on ethanol-induced iron overload and liver damage, focusing on the signaling pathway of the iron regulatory hormone hepcidin. Adult male C57BL/6J mice were pair-fed with isocaloric-Lieber De Carli diets containing ethanol (accounting for 30% of total calories) and/or carbonyl iron (0.2%) and treated with quecertin (100 mg/kg body weight) for 15 weeks. Mouse primary hepatocytes were incubated with ethanol (100 mM) and quercetin (100 μM) for 24 h. Mice exposed to either ethanol or iron presented significant fatty infiltration and iron deposition in the liver; these symptoms were exacerbated in mice cotreated with ethanol and iron. Quercetin attenuated the abnormity induced by ethanol and/or iron. Ethanol suppressed BMP6 and intranuclear SMAD4 as well as decreased hepcidin expression. These effects were partially alleviated by quercetin supplementation in mice and hepatocytes. Importantly, ethanol caused suppression of SMAD4 binding to the HAMP promoter and of hepcidin messenger RNA expression. These effects were exacerbated by anti-BMP6 antibody and partially alleviated by quercetin or human recombinant BMP6 in cultured hepatocytes. In contrast, co-treatment with iron and ethanol, especially exposure of iron alone, activated BMP6/SMAD4 pathway and up-regulated hepcidin expression, which was also normalized by quercetin in vivo. Quercetin prevented ethanol-induced hepatic iron overload different from what carbonyl iron diet elicited in the mechanism, by regulating hepcidin expression via the BMP6/SMAD4 signaling pathway., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Emerging evidence has displayed that oxygen free radicals especially ones promoted by "free" iron play an important role in the development of alcoholic liver disease (ALD). Naturally-occurring quercetin has been reported to prevent ALD and iron overload-induced damage aside from the "free" iron. The purpose was to explore the potential mechanisms by which quercetin arrests alcohol-induced "free" iron disorder. Chronic alcohol (30% of total calories) or iron (0.2%)-fed adult male C57BL/J mice for 15 weeks resulted in significantly elevated levels of hepatic iron, labile iron pool-Fe and serum non-transferrin bound iron, accompanied with sustained oxidative damage. The hepatotoxicity was further exacerbated by ethanol and iron. Quercetin (100 mg/kg. body weight) alleviated the detrimental effects induced by ethanol and/or iron. The expressions of divalent metal transporter 1, zinc transporter member 14, mucolipin 1, transferrin receptor 1 (TfR1) and ferritin were up-regulated by ethanol and/or iron, which were partially normalized by quercetin. Quercetin prevented ethanol-induced hepatotoxicity, which may be partially attributed to the alleviated disorder of bound iron and "free" iron. The significant suppression of ethanol-stimulated molecules for "free" iron uptake and release may contribute to the hepatoprotective effect of quercetin, although TfR1-mediated physiological pathway of iron uptake also played a role., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Introduction: Oxidative stress plays a pivotal role in the intense exercise-induced myocardium injury, and mitochondrial compartment is presumed as the main source and susceptible target of intracellular reactive oxygen species (ROS)., Purpose: The objective of this study was to evaluate the protective effect of quercetin, a naturally occurring flavonoids possessing antioxidant effect on repeated intense exercise-induced mitochondrial oxidative stress and dysfunction., Methods: Adult male BALB/C mice were treated by quercetin (100 mg/kg bw) for 4 weeks and subjected to the exercise protocol on a treadmill (28 m/min at 5° slope for 90 min) for seven consecutive days concurrently at the fourth week., Results: Intense exercise in mice resulted in the leakage of creatine kinase-MB (increased from 221.5 ± 33.8 to 151.1 ± 19.1 U/l, P < 0.01) and ultrastructural malformation mainly evidenced by disrupted myofibrils and swollen mitochondria, which was overtly attenuated by quercetin prophylaxis. Quercetin pretreatment evidently alleviated mitochondrial oxidative stress by inhibiting glutathione depletion and aconitase inactivation, ROS over-generation, and lipid peroxidation in cardiac mitochondria of intense exercise mice. Furthermore, mitochondrial dysfunction manifested by decreased mitochondrial membrane potential (68.6 ± 7.6 versus 100.0 ± 7.7 %, P < 0.01) and respiratory control ratio (5.03 ± 0.55 versus 7.48 ± 0.71, P < 0.01) induced as a consequence of acute exercise was markedly mitigated by quercetin precondition., Conclusion: Quercetin protects mouse myocardium against intense exercise injury, especially ultrastructural damage and mitochondrial dysfunction, probably through its beneficial antioxidative effect, highlighting a promising strategy for over-training injury by naturally occurring phytochemicals.

Nanobiotechnology has been recently viewed as a promising strategy to improve therapy efficacy by promoting the accumulation of hydrophobic bioactive compounds in tissues. The aim of present study was to formulate a novel quercetin-loaded cationic nanostructured lipid carriers (QR-CNLC) and to evaluate its biodistribution in vivo after oral administration. QR-CNLC were prepared by emulsifying at high temperature and subsequent solidifying at low temperature using various functional ingredients, and its characteristics, including physical index, release profile in vitro, and tissue distribution in vivo, were investigated. The results demonstrated that QR-CNLC exhibited an average particle size 126.6 nm, a zeta potential of 40.5 mV and 89.3% entrapment efficiency. QR-CNLC performed slower release compared with quercetin solution in vitro. QR-CNLC showed higher AUC (area under tissue concentration-time curve) value and higher Cmax value in lung, liver and kidney compared with control group. The value of relative intake rate (re) for lung, liver and kidney was 1.57, 1.51 and 1.68, respectively, which revealed that quercetin can be significantly accumulated in lung, kidney and liver after oral administration of QR-CNLC compared with quercetin suspension. In conclusion, cationic nanostructured lipid carriers may be an attractive nanocarrier system for oral delivery of hydrophobic functional components., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Naturally occuring quercetin protects hepatocytes from ethanol-induced oxidative stress, and heme oxygenase-1 (HO-1) induction and carbon monoxide (CO) metabolite may be implicated in the beneficial effect. However, the precise mechanism by which quercetin counteracts CYP2E1-mediated ethanol hepatotoxicity through HO-1 system is still remained unclear. To explore the potential mechanism, herein, ethanol (4.0 g/kg.bw.) was administrated to rats for 90 days. Our data showed that chronic ethanol over-activated CYP2E1 but suppressed HO-1 with concurrent hepatic oxidative damage, which was partially normalized by quercetin (100mg/kg.bw.). Quercetin (100 μM) induced HO-1 and depleted heme pool when incubated to human hepatocytes. Ethanol-stimulated (100mM) CYP2E1 upregulation was suppressed by quercetin but further enhanced by HO-1 inhibition with resultant heme accumulation. CO scavenging blocked the suppression of quercetin only on CYP2E1 activity. CO donor dose-dependently inactivated CYP2E1 of ethanol-incubated microsome, which was mimicked by HO-1 substrate but abolished by CO scavenger. Thus, CYP2E1-mediated ethanol hepatotoxicity was alleviated by quercetin through HO-1 induction. Depleted heme pool and CO releasing limited protein synthesis and inhibited enzymatic activity of CYP2E1, respectively., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

To attenuate alcohol liver disease (ALD) is extremely urgent since ALD has been emerged as a major liver disease. The aim of the present study is to investigate the hepatoprotective effect against ethanol-induced injury of bilirubin, a product of heme metabolism degradation via HO and biliverdin reductase catalysis. Ethanol-incubated primary rat hepatocytes (100 mmol/L) were treated by quercetin, bilirubin, inflammatory factors, and/or HO-1 inducer/inhibitor for 24 h, and the cellular damage was assayed. Quercetin lowered ethanol-induced glutathione depletion and superoxide dismutase inactivation, inhibited the overproduction of malondialdehyde and reactive oxygen species, and decreased the leakage of cellular aspartate aminotransferase and lactate dehydrogenase, accompanying the normalization of bilirubin level. The effect of quercetin was mimicked by exogenous bilirubin in a dose-dependent manner to some extent (within 25 μmol/L) and pharmacological HO-1 inducer hemin, but abolished by HO-1 inhibitor zinc protoporphyrin-IX. Inflammatory challenge of TNF-α plus IL-6 further aggravated ethanol-induced oxidative damage, which was also attenuated by bilirubin in part. These findings shed a light on the anti-oxidative and anti-inflammatory role of bilirubin released from quercetin/HO-1 and biliverdin reductase pathway against ethanol hepatotoxicity and highlight a prospective strategy of nutritional intervention for ALD by naturally occurring quercetin to induce HO-1 with the release of bioactive end-products., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Lipid metabolism disorder and oxidative stress play an important role on the development and progression of alcoholic liver disease (ALD), and mitochondria compartment is presumed as the main source and susceptible target of intracellular ROS. The objective of this study was to evaluate the protective effect of quercetin, a naturally occurring flavonoids possessing both antioxidant and hypolipidemic effect, on ethanol-induced dyslipidemia and oxidative damage focused on mitochondria. Chronic alcohol administration for adult male rats (4.0 g/kg for 90 days) resulted in the leakage of alanine and especially aspartate aminotransferases, and morphological malformation mainly evidenced by sustained lipid infiltration and degenerative changes on mitochondria and rough endoplasmic reticulum, which was markedly alleviated by quercetin (100 mg/kg.bw.) pretreatment. Furthermore, quercetin prophylaxis evidently ameliorated ethanol-stimulated mitochondrial dysfunction manifested by decreased membrane potential and induced permeability transition though suppressing glutathione depletion, enzymatic inactivation of manganese superoxide dismutase and glutathione peroxidase, ROS over-generation, and lipid peroxidation in mitochondria. Quercetin, thus, may protect rat, especially hepatic mitochondria, from chronic ethanol toxicity through its hypolipidemic effect and antioxidative role, highlighting a promising preventive strategy for ALD by naturally occurring phytochemicals., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Graphical abstract Highlights • Quercetin is a natural functional component distributed in vegetables, fruits and red wine. • Lysosome damage mediated autophagy dysfunction played an important role in ALD. • Quercetin promoted TFEB nuclear translocation to enhance lysosomal function. • mTOR-TFEB pathway may be a major mechanism of the protection of quercetin. Abstract This study aimed to investigate the effects of quercetin that is natural functional component in food on lysosome damage-mediated autophagy dysfunction in ALD and its possible underlying mechanisms. The C57BL/6J mice were divided into four groups and pair-fed with either regular or ethanol-containing Lieber De Carli liquids diets for 15 weeks. Quercetin was received by gavage. According to the purpose of experiments, primary hepatocytes were pretreated with various pharmacological reagents. Results showed that quercetin alleviated chronic ethanol consumption induced liver injury and autophagic flux suppression. Quercetin decreased the abnormal LC3-II and p62 accumulation and increased the expression of LAMP1, LAMP2 and Rab7. Besides, quercetin reversed the inhibition of TFEB nuclear translocation incited by ethanol and exhibited similar effect to Torin 1 (mTOR activity inhibitor) which could promote TFEB nuclear translocation. Thus, regulating mTOR-TFEB pathway may be a major mechanism of quercetin for ameliorating lysosomal autophagy dysfunction induced by ethanol. [ABSTRACT FROM AUTHOR]

Abstract: As the main source of reactive oxygen species (ROS), hepatic microsomes are susceptible to ROS attack, especially upon CYP2E1 activation by ethanol. The objective of this study was to evaluate the hepatoprotective effect of quercetin, by inducing haem oxygenase-1 (HO-1), on ethanol-induced microsomal oxidative stress. Chronic alcohol administration to adult rats (4.0g/kg for 90days) resulted in microsomal redox disturbance and liver dysfunction, accompanying CYP2E1 upregulation and HO-1 downregulation of both protein expression and enzymatic activity. Quercetin (100mg/kg) induced HO-1, which was not completely suppressed by ethanol. Moreover, quercetin pretreatment to ethanol-fed rats lowered CYP2E1 induction, partially normalised ethanol-overwhelmed microsomal antioxidative system, decreased ROS level and lipid peroxidation, and alleviated the leakage of transaminases. Given the beneficial effect of HO-1, its induction by quercetin may contribute to the protective role against CYP2E1-mediated oxidative stress on hepatic microsomes. [Copyright &y& Elsevier]

Alcoholic liver disease (ALD), a spectrum of liver abnormalities induced by chronic alcohol abuse, continues to be the major cause of life-threatening liver disease in developed countries. Autophagy and exosomes were individually confirmed to be involved in the pathogenesis of ALD. Here, we sought to identify the role of autophagy and exosomes in the liver protective effects of quercetin. We observed decreased hepatic LC3II/LC3I and increased p62 level in ethanol-fed mice, and these changes were alleviated by quercetin. Meanwhile, nanoparticle tracking analysis (NTA) showed elevated serum exosomes numbers in ethanol-fed mice, which was combated by quercetin. Ethanol induced elevated LDH, ALT, and AST in HepG2 supernatant, which was alleviated by cytochalasin D (exosomes uptake inhibitor). Moreover, quercetin reduced ethanol-induced LDH and ALT elevation in vitro, and the effects of quercetin were reversed by Rab27a overexpression (induce exosomes release) or wortmannin treatment (autophagy inhibitor). Transcriptomic analysis supported that quercetin reversed the change of lysosome related genes disturbed by ethanol. Meanwhile, western blot analysis exhibited decreased hepatic expression of LAMP2 and ATPA6V1B2, and active Cathepsin B/Cathepsin B by quercetin treatment, indicating quercetin alleviated lysosome dysfunction in ethanol-fed mice. Baf A treatment or transfection of siTFEB offset quercetin's effects in ethanol-induced LDH and ALT elevation, exosomes release, and autophagy inhibition (LC3II/I and p62 accumulation). Taken together, quercetin coordinately activates autophagy and combats exosomes release by restoring lysosome function, and further mitigates ethanol-induced liver damage. [ABSTRACT FROM AUTHOR]