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Alcoholic liver disease (ALD) is one of the severe liver diseases, resulting in high morbidity and mortality. However, frataxin, a mitochondrial protein mainly participating in iron homeostasis and oxidative stress, remains uncertain in the pathogenesis of ALD. In the present study, the role of frataxin in ALD was investigated. Ethanol (100 mM) decreased frataxin expression at 48 and 72 h in HepG2. Dramatically, in HepG2 overexpressing cytochrome P450 2E1 (HepG2 CYP2E1+/+ ), frataxin level was down-regulated with ethanol stimulation at 12 h. Moreover, chronically feeding ethanol to mice via Lieber-DeCarli liquid diet (30 % of total calories) for 15 weeks significantly inhibited frataxin expression. Ferroptosis signature proteins were dysregulated, accompanied by mitochondrial damage of morphology, enhanced malondialdehyde and decreased glutathione in the liver, as well as accumulation of reactive oxygen species and mitochondrial labile iron pool in primary hepatocytes. Notably, proteomics screening of frataxin deficient-HepG2 further suggested frataxin was associated with ferroptosis. Furthermore, the ferroptosis inhibitor ferrostatin-1 blocked the increase of lactate dehydrogenase release by ethanol in HepG2 CYP2E1+/+ . Most importantly, frataxin deficiency enhanced ferroptosis driven by ethanol via evaluating the levels of lactate dehydrogenase, cell morphological changes, mitochondrial labile iron pool, and lipid peroxidation. Conversely, restoring frataxin alleviated the sensitivity to ferroptosis. In addition, frataxin overexpression mitigated the sensitivity of ethanol-induced ferroptosis in HepG2 CYP2E1+/+ . Collectively, our study revealed that frataxin-mediated ferroptosis contributed to ALD, highlighting a potential therapeutic strategy for ALD., (Copyright © 2020 Elsevier B.V. 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.)

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.

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.)

Stress-inducible protein heme oxygenase-1(HO-1) is well-appreciative to counteract oxidative damage and inflammatory stress involving the pathogenesis of alcoholic liver diseases (ALD). The potential role and signaling pathways of HO-1 metabolite carbon monoxide (CO), however, still remained unclear. To explore the precise mechanisms, ethanol-dosed adult male Balb/c mice (5.0g/kg.bw.) or ethanol-incubated primary rat hepatocytes (100mmol/L) were pretreated by tricarbonyldichlororuthenium (II) dimmer (CORM-2, 8mg/kg for mice or 20μmol/L for hepatocytes), as well as other pharmacological reagents. Our data showed that CO released from HO-1 induction by quercetin prevented ethanol-derived oxidative injury, which was abolished by CO scavenger hemoglobin. The protection was mimicked by CORM-2 with the attenuation of GSH depletion, SOD inactivation, MDA overproduction, and the leakage of AST, ALT or LDH in serum and culture medium induced by ethanol. Moreover, CORM-2 injection or incubation stimulated p38 phosphorylation and suppressed abnormal Tnfa and IL-6, accompanying the alleviation of redox imbalance induced by ethanol and aggravated by inflammatory factors. The protective role of CORM-2 was abolished by SB203580 (p38 inhibitor) but not by PD98059 (ERK inhibitor) or SP600125 (JNK inhibitor). Thus, HO-1 released CO prevented ethanol-elicited hepatic oxidative damage and inflammatory stress through activating p38 MAPK pathway, suggesting a potential therapeutic role of gaseous signal molecule on ALD induced by naturally occurring phytochemicals., (© 2013. Published by Elsevier Inc. 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: 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 &y& Elsevier]

Abstract: 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 (4.0g/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 (100μM) 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 &y& Elsevier]

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]