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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.)

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.

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.

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.)

Objective: Senescence of vascular cells contributes to the development of cardiovascular diseases and the overall aging. This study was undertaken to investigate the effects of resveratrol (Res) on amelioration of vascular cell aging and the role of SIRT1/nicotinamide adenine dinucleotide phosphate (NADPH) oxidase pathway., Methods and Results: Adult male Wistar rats were treated with a high-fat/sucrose diet (HFS) in the presence or absence of Res for 3 months. HFS and in vitro treatment with high glucose increased the senescence cells and reactive oxygen species production in rat aorta and cultured bovine aortic endothelial cells (BAECs), respectively, which was attenuated by Res treatment. Res protected against HFS- or high-glucose-induced increase in NADPH oxidase p47phox expression and decrease in SIRT1 level. Apocynin, a NADPH oxidase inhibitor, down-regulated p47phox protein expression, but had no influence on SIRT1 protein; sirtinol, a SIRT1 inhibitor, aggravated the decrease in SIRT1 protein level and the increase in p47phox protein expression induced by high glucose., Conclusion: Our studies suggested that Res was able to reverse the senescence process in aorta induced by HFS in rats or induced by the exposure to high glucose in cultured BAECs. The underlying mechanism is at least SIRT1/NADPH oxidase pathway dependent., (Copyright © 2012 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.)

Highlights: [•] Quercetin counteracted ethanol-derived hepatic oxidative stress and liver damage. [•] Quercetin alleviated ethanol-induced liver iron overload and “free” iron disorder. [•] Quercetin inhibited ethanol-stimulated DMT1, ZIP14 and TRPML1 responsible for “free” iron uptake and release. [•] In addition, quercetin suppressed ethanol-stimulated TfR1 and Ft light chain expression. [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]

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. [ABSTRACT FROM AUTHOR]