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Antioxidant Agents for the Prevention and Therapy of Oxidative Stress in Hepatic Diseases

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (15 August 2021) | Viewed by 30652

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Special Issue Editors

Dr. Teresa Carbonell Camós

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Guest Editor

Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain
Interests: oxidants and antioxidants in physiology; intermittent hypoxia and neuroprotection in postischemic processes; molecular mechanisms induced by hypothermia in isolated rat liver
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Joan Roselló-Catafau

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Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Catalonia, Spain
Interests: liver transplantation; inflammation; ischemia reperfusion injury
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oxidative stress has been implicated in diverse pathological mechanisms, and may contribute to the initiation and progression of liver injury. Risk factors including drugs and alcohol, environmental pollutants and irradiation, and exposure to viruses and bacteria may generate reactive oxygen species (ROS). This results in severe hepatic diseases, such as alcoholic liver disease and non-alcoholic fatty liver disease (NAFLD). Increased ROS production is also involved in ischemia–reperfusion injury (IRI) pathology. IRI is an inherent syndrome associated with liver surgery and organ transplantation where deleterious injury is due to ischemia (oxygen deprivation) and reperfusion (blood and oxygen restoration).

Antioxidant therapy would mean a rational healing strategy in the treatment of liver diseases that involve ROS production. There is a growing interest in the application of natural antioxidants and in the use of antioxidant chemicals to improve or prevent liver disease. For potential new therapeutic targets, more emphasis should be placed on deeper mechanistic investigations of hepatic ischemia–reperfusion injury and on translational research to refine current strategies in the use of antioxidants.

This Special Issue calls for original research and full reviews that address the progress and current knowledge on the mechanism of ROS-mediated liver injury, therapeutic strategies, and the protective role of antioxidants.

Detailed investigations on the mechanism of ROS-mediated liver disease could open new insights for the development of biomarkers and therapeutic approaches.

Contributions need not be limited to the fields mentioned in the keywords.

Dr. Teresa Carbonell Camós
Prof. Dr. Joan Roselló-Catafau
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Antioxidant therapeutic strategies
Inflammation, autophagy, and apoptosis
Ischemia and reperfusion injury
Liver transplantation
Natural and chemical antioxidants
Non-alcoholic fatty liver disease (NAFLD)

Published Papers (9 papers)

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Research

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14 pages, 1810 KiB

Open AccessArticle

PEG35 and Glutathione Improve Mitochondrial Function and Reduce Oxidative Stress in Cold Fatty Liver Graft Preservation

by Raquel G. Bardallo, Idoia Company-Marin, Emma Folch-Puy, Joan Roselló-Catafau, Arnau Panisello-Rosello and Teresa Carbonell

Antioxidants 2022, 11(1), 158; https://doi.org/10.3390/antiox11010158 - 14 Jan 2022

Cited by 11 | Viewed by 2476

Abstract

The need to meet the demand for transplants entails the use of steatotic livers, more vulnerable to ischemia-reperfusion (IR) injury. Therefore, finding the optimal composition of static cold storage (SCS) preservation solutions is crucial. Given that ROS regulation is a therapeutic strategy for liver IR injury, we have added increasing concentrations of PEG35 and glutathione (GSH) to the preservation solutions (IGL-1 and IGL-2) and evaluated the possible protection against energy depletion and oxidative stress. Fatty livers from obese Zücker rats were isolated and randomly distributed in the control (Sham) preserved (24 h at 4 °C) in IGL-0 (without PEG35 and 3 mmol/L GSH), IGL-1 (1 g/L PEG35, and 3 mmol/L GSH), and IGL-2 (5 g/L PEG35 and 9 mmol/L GSH). Energy metabolites (ATP and succinate) and the expression of mitochondrial oxidative phosphorylation complexes (OXPHOS) were determined. Mitochondrial carrier uncoupling protein 2 (UCP2), PTEN-induced kinase 1 (PINK1), nuclear factor-erythroid 2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and the inflammasome (NLRP3) expressions were analyzed. As biomarkers of oxidative stress, protein oxidation (AOPP) and carbonylation (DNP derivatives), and lipid peroxidation (malondialdehyde (MDA)–thiobarbituric acid (TBA) adducts) were measured. In addition, the reduced and oxidized glutathione (GSH and GSSG) and enzymatic (Cu–Zn superoxide dismutase (SOD), CAT, GSH S-T, GSH-Px, and GSH-R) antioxidant capacities were determined. Our results showed that the cold preservation of fatty liver graft depleted ATP, accumulated succinate and increased oxidative stress. In contrast, the preservation with IGL-2 solution maintained ATP production, decreased succinate levels and increased OXPHOS complexes I and II, UCP2, and PINK-1 expression, therefore maintaining mitochondrial integrity. IGL-2 also protected against oxidative stress by increasing Nrf2 and HO-1 expression and GSH levels. Therefore, the presence of PEG35 in storage solutions may be a valuable option as an antioxidant agent for organ preservation in clinical transplantation. Full article

(This article belongs to the Special Issue Antioxidant Agents for the Prevention and Therapy of Oxidative Stress in Hepatic Diseases)

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20 pages, 8010 KiB

Open AccessArticle

Vitamin C Deficiency May Delay Diet-Induced NASH Regression in the Guinea Pig

by Josephine Skat-Rørdam, Kamilla Pedersen, Gry Freja Skovsted, Ida Gregersen, Sara Vangsgaard, David H. Ipsen, Markus Latta, Jens Lykkesfeldt and Pernille Tveden-Nyborg

Antioxidants 2022, 11(1), 69; https://doi.org/10.3390/antiox11010069 - 28 Dec 2021

Cited by 5 | Viewed by 2198

Abstract

Oxidative stress is directly linked to non-alcoholic fatty liver disease (NAFLD) and the progression to steaotohepatitis (NASH). Thus, a beneficial role of antioxidants in delaying disease progression and/or accelerating recovery may be expected, as corroborated by recommendations of, e.g., vitamin E supplementation to patients. This study investigated the effect of vitamin C deficiency—often resulting from poor diets low in fruits and vegetables and high in fat—combined with/without a change to a low fat diet on NAFLD/NASH phenotype and hepatic transcriptome in the guinea pig NASH model. Vitamin C deficiency per se did not accelerate disease induction. However, the results showed an effect of the diet change on the resolution of hepatic histopathological hallmarks (steatosis, inflammation, and ballooning) (p < 0.05 or less) and indicated a positive effect of a high vitamin C intake when combined with a low fat diet. Our data show that a diet change is important in NASH regression and suggest that a poor vitamin C status delays the reversion towards a healthy hepatic transcriptome and phenotype. In conclusion, the findings support a beneficial role of adequate vitamin C intake in the regression of NASH and may indicate that vitamin C supplementation in addition to lifestyle modifications could accelerate recovery in NASH patients with poor vitamin C status. Full article

(This article belongs to the Special Issue Antioxidant Agents for the Prevention and Therapy of Oxidative Stress in Hepatic Diseases)

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13 pages, 2592 KiB

Open AccessArticle

Comparative Analysis of the Antioxidative and Hepatoprotective Activities of Dimethyl Diphenyl Bicarboxylate in Four Animal Models of Hepatic Injury

by Jing-Hua Wang, Seung-Ju Hwang and Chang-Gue Son

Antioxidants 2021, 10(10), 1508; https://doi.org/10.3390/antiox10101508 - 23 Sep 2021

Cited by 4 | Viewed by 2039

Abstract

As a well-known hepatoprotective and antioxidant agent, dimethyl diphenyl bicarboxylate (DDB) has frequently been employed to remedy various liver diseases. However, it is still uncertain whether DDB exerts consistent hepatoprotective and antioxidative activities against varying degrees of hepatic damage. Therefore, DDB (100, 25, 5, or 50 mg/kg depending on the model) was administered to animals in four representative models of liver injury (CCl₄ chemical acute model, DMN subchronic model, TAA chronic model, and restraint stress psychological acute model). Horizontal comparative analysis indicated that DDB significantly lowered the excess serum AST and ALT levels in the CCl₄ and DMN models but not in the TAA and restraint stress models. In accordance with this result, DDB markedly reduced oxidative stress indices (hepatic MDA and ROS) but restored five main antioxidant components (GSH content, GSH-peroxidase, GSH-reductase, SOD, and catalase activity) in the CCl₄ and DMN models. DDB failed to normalize oxidative stressors in the restraint stress-induced injury model and restore these five antioxidant components in the TAA model. Overall, our results produced a comprehensive overview of the effects of DDB on oxidative stressors and the main antioxidative components using four animal models. These findings will provide valuable clues to guide therapeutic clinical applications. Full article

(This article belongs to the Special Issue Antioxidant Agents for the Prevention and Therapy of Oxidative Stress in Hepatic Diseases)

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16 pages, 2575 KiB

Open AccessArticle

Curcumin Suppresses the Lipid Accumulation and Oxidative Stress Induced by Benzo[a]pyrene Toxicity in HepG2 Cells

by Seung-Cheol Lee, Seung-Cheol Jee, Min Kim, Soee Kim, Min Kyoung Shin, Yunkyung Kim and Jung-Suk Sung

Antioxidants 2021, 10(8), 1314; https://doi.org/10.3390/antiox10081314 - 20 Aug 2021

Cited by 15 | Viewed by 3956

Abstract

Benzo[a]pyrene (B[a]P) is a potentially hepatotoxic group-1 carcinogen taken up by the body through ingestion of daily foods. B[a]P is widely known to cause DNA and protein damages, which are closely related to cell transformation. Accordingly, studies on natural bioactive compounds that attenuate such chemical-induced toxicities have significant impacts on public health. This study aimed to uncover the mechanism of curcumin, the major curcuminoid in turmeric (Curcuma longa), in modulating the lipid accumulation and oxidative stress mediated by B[a]P cytotoxicity in HepG2 cells. Curcumin treatment reduced the B[a]P-induced lipid accumulation and reactive oxygen spicies (ROS) upregulation and recovered the cell viability. Cytochrome P450 family 1 subfamily A polypeptide 1 (CYP1A1) and Cytochrome P450 subfamily B polypeptide 1 (CYP1B1) downregulation resulting from decreased aryl hydrocarbon receptor (AhR) translocation into nuclei attenuated the effects of B[a]P-induced lipid accumulation and repressed cell viability, respectively. Moreover, the curcumin-induced reduction in ROS generation decreased the nuclear translocation of Nuclear factor erythroid-2-related factor 2 (Nrf2) and the expression of phase-II detoxifying enzymes. These results indicate that curcumin suppresses B[a]P-induced lipid accumulation and ROS generation which can potentially induce nonalcoholic fatty liver disease (NAFLD) and can shed a light on the detoxifying effect of curcumin. Full article

(This article belongs to the Special Issue Antioxidant Agents for the Prevention and Therapy of Oxidative Stress in Hepatic Diseases)

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16 pages, 3120 KiB

Open AccessArticle

Acyl Quinic Acid Derivatives Screened Out from Carissa spinarum by SOD-Affinity Ultrafiltration LC–MS and Their Antioxidative and Hepatoprotective Activities

by Ye Liu, Felix Wambua Muema, Yong-Li Zhang and Ming-Quan Guo

Antioxidants 2021, 10(8), 1302; https://doi.org/10.3390/antiox10081302 - 18 Aug 2021

Cited by 10 | Viewed by 2557

Abstract

Carissa spinarum Linn. has been utilized both in the food industry and as a traditional medicine for various ailments, while the responsible chemical components and action mechanisms of its antioxidative and hepatoprotective activities remain unclear. In this work, at least 17 quinic acid derivatives as potential ligands for the superoxide dismutase (SOD) enzyme from Carissa spinarum L. were screened out using the bio-affinity ultrafiltration with liquid chromatography mass spectrometry (UF–LC/MS), and 12 of them (1–12), including, three new ones (1–3), were further isolated by phytochemical methods and identified by high resolution electrospray ionization mass spectrometry (HR-ESI-MS) and extensive nuclear magnetic resonance (NMR) spectroscopic analysis. All of these isolated compounds were evaluated for their antioxidant activities by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and ferric-reducing antioxidant power (FRAP) methods. As a result, compounds 4 and 6–11 displayed similar or better antioxidant activities compared to vitamin C, which is in good agreement with the bio-affinity ultrafiltration with SOD enzyme. Then, these compounds, 4 and 6–11, with better antioxidant activity were further explored to protect the L02 cells from H₂O₂-induced oxidative injury by reducing the reactive oxygen species (ROS) and Malondialdehyde (MDA) production and activating the SOD enzyme. To the best of our knowledge, this is the first report to use an efficient ultrafiltration approach with SOD for the rapid screening and identification of the SOD ligands directly from a complex crude extract of Carissa spinarum, and to reveal its corresponding active compounds with good antioxidative and hepatoprotective activities. Full article

(This article belongs to the Special Issue Antioxidant Agents for the Prevention and Therapy of Oxidative Stress in Hepatic Diseases)

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14 pages, 3226 KiB

Open AccessArticle

Luteolin Alleviates AflatoxinB₁-Induced Apoptosis and Oxidative Stress in the Liver of Mice through Activation of Nrf2 Signaling Pathway

by Shahid Ali Rajput, Aftab Shaukat, Kuntan Wu, Imran Rashid Rajput, Dost Muhammad Baloch, Rana Waseem Akhtar, Muhammad Asif Raza, Agnieszka Najda, Papliński Rafał, Ashraf Albrakati, Attalla F. El-Kott and Mohamed M. Abdel-Daim

Antioxidants 2021, 10(8), 1268; https://doi.org/10.3390/antiox10081268 - 09 Aug 2021

Cited by 47 | Viewed by 3818

Abstract

Aflatoxin B₁ (AFB₁), a threatening mycotoxin, usually provokes oxidative stress and causes hepatotoxicity in animals and humans. Luteolin (LUTN), well-known as an active phytochemical agent, acts as a strong antioxidant. This research was designed to investigate whether LUTN exerts protective effects against AFB₁-induced hepatotoxicity and explore the possible molecular mechanism in mice. A total of forty-eight mice were randomly allocated following four treatment groups (n = 12): Group 1, physiological saline (CON). Group 2, treated with 0.75 mg/kg BW aflatoxin B₁ (AFB₁). Group 3, treated with 50 mg/kg BW luteolin (LUTN), and Group 4, treated with 0.75 mg/kg BW aflatoxin B₁ + 50 mg/kg BW luteolin (AFB₁ + LUTN). Our findings revealed that LUTN treatment significantly alleviated growth retardation and rescued liver injury by relieving the pathological and serum biochemical alterations (ALT, AST, ALP, and GGT) under AFB₁ exposure. LUTN ameliorated AFB₁-induced oxidative stress by scavenging ROS and MDA accumulation and boosting the capacity of the antioxidant enzyme (CAT, T-SOD, GSH-Px and T-AOC). Moreover, LUTN treatment considerably attenuates the AFB₁-induced apoptosis in mouse liver, as demonstrated by declined apoptotic cells percentage, decreased Bax, Cyt-c, caspase-3 and caspase-9 transcription and protein with increased Bcl-2 expression. Notably, administration of LUTN up-regulated the Nrf2 and its associated downstream molecules (HO-1, NQO1, GCLC, SOD1) at mRNA and protein levels under AFB₁ exposure. Our results indicated that LUTN effectively alleviated AFB₁-induced liver injury, and the underlying mechanisms were associated with the activation of the Nrf2 signaling pathway. Taken together, LUTN may serve as a potential mitigator against AFB₁-induced liver injury and could be helpful for the development of novel treatment to combat liver diseases in humans and/or animals. Full article

(This article belongs to the Special Issue Antioxidant Agents for the Prevention and Therapy of Oxidative Stress in Hepatic Diseases)

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19 pages, 4249 KiB

Open AccessArticle

Effects of C60 Fullerene on Thioacetamide-Induced Rat Liver Toxicity and Gut Microbiome Changes

by Siniša Đurašević, Snežana Pejić, Ilijana Grigorov, Gorana Nikolić, Dragana Mitić-Ćulafić, Milan Dragićević, Jelena Đorđević, Nevena Todorović Vukotić, Neda Đorđević, Ana Todorović, Dunja Drakulić, Filip Veljković, Snežana B. Pajović and Zoran Todorović

Antioxidants 2021, 10(6), 911; https://doi.org/10.3390/antiox10060911 - 04 Jun 2021

Cited by 12 | Viewed by 3611

Abstract

Thioacetamide (TAA) is widely used to study liver toxicity accompanied by oxidative stress, inflammation, cell necrosis, fibrosis, cholestasis, and hepatocellular carcinoma. As an efficient free radical’s scavenger, C60 fullerene is considered a potential liver-protective agent in chemically-induced liver injury. In the present work, we examined the hepatoprotective effects of two C60 doses dissolved in virgin olive oil against TAA-induced hepatotoxicity in rats. We showed that TAA-induced increase in liver oxidative stress, judged by the changes in the activities of SOD, CAT, GPx, GR, GST, the content of GSH and 4-HNE, and expression of HO-1, MnSOD, and CuZnSOD, was more effectively ameliorated with a lower C60 dose. Improvement in liver antioxidative status caused by C60 was accompanied by a decrease in liver HMGB1 expression and an increase in nuclear Nrf2/NF-κB p65 ratio, suggesting a reduction in inflammation, necrosis and fibrosis. These results were in accordance with liver histology analysis, liver comet assay, and changes in serum levels of ALT, AST, and AP. The changes observed in gut microbiome support detrimental effects of TAA and hepatoprotective effects of low C60 dose. Less protective effects of a higher C60 dose could be a consequence of its enhanced aggregation and related pro-oxidant role. Full article

(This article belongs to the Special Issue Antioxidant Agents for the Prevention and Therapy of Oxidative Stress in Hepatic Diseases)

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Review

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14 pages, 11363 KiB

Open AccessReview

Preventing Oxidative Stress in the Liver: An Opportunity for GLP-1 and/or PASK

by Verónica Hurtado-Carneiro, Pilar Dongil, Ana Pérez-García, Elvira Álvarez and Carmen Sanz

Antioxidants 2021, 10(12), 2028; https://doi.org/10.3390/antiox10122028 - 20 Dec 2021

Cited by 8 | Viewed by 3982

Abstract

The liver’s high metabolic activity and detoxification functions generate reactive oxygen species, mainly through oxidative phosphorylation in the mitochondria of hepatocytes. In contrast, it also has a potent antioxidant mechanism for counterbalancing the oxidant’s effect and relieving oxidative stress. PAS kinase (PASK) is a serine/threonine kinase containing an N-terminal Per-Arnt-Sim (PAS) domain, able to detect redox state. During fasting/feeding changes, PASK regulates the expression and activation of critical liver proteins involved in carbohydrate and lipid metabolism and mitochondrial biogenesis. Interestingly, the functional inactivation of PASK prevents the development of a high-fat diet (HFD)-induced obesity and diabetes. In addition, PASK deficiency alters the activity of other nutrient sensors, such as the AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR). In addition to the expression and subcellular localization of nicotinamide-dependent histone deacetylases (SIRTs). This review focuses on the relationship between oxidative stress, PASK, and other nutrient sensors, updating the limited knowledge on the role of PASK in the antioxidant response. We also comment on glucagon-like peptide 1 (GLP-1) and its collaboration with PASK in preventing the damage associated with hepatic oxidative stress. The current knowledge would suggest that PASK inhibition and/or exendin-4 treatment, especially under fasting conditions, could ameliorate disorders associated with excess oxidative stress. Full article

(This article belongs to the Special Issue Antioxidant Agents for the Prevention and Therapy of Oxidative Stress in Hepatic Diseases)

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23 pages, 12723 KiB

Open AccessFeature PaperReview

Cerium Oxide Nanoparticles: A New Therapeutic Tool in Liver Diseases

by Gregori Casals, Meritxell Perramón, Eudald Casals, Irene Portolés, Guillermo Fernández-Varo, Manuel Morales-Ruiz, Victor Puntes and Wladimiro Jiménez

Antioxidants 2021, 10(5), 660; https://doi.org/10.3390/antiox10050660 - 24 Apr 2021

Cited by 40 | Viewed by 4406

Abstract

Oxidative stress induced by the overproduction of free radicals or reactive oxygen species (ROS) has been considered as a key pathogenic mechanism contributing to the initiation and progression of injury in liver diseases. Consequently, during the last few years antioxidant substances, such as superoxide dismutase (SOD), resveratrol, colchicine, eugenol, and vitamins E and C have received increasing interest as potential therapeutic agents in chronic liver diseases. These substances have demonstrated their efficacy in equilibrating hepatic ROS metabolism and thereby improving liver functionality. However, many of these agents have not successfully passed the scrutiny of clinical trials for the prevention and treatment of various diseases, mainly due to their unspecificity and consequent uncontrolled side effects, since a minimal level of ROS is needed for normal functioning. Recently, cerium oxide nanoparticles (CeO₂NPs) have emerged as a new powerful antioxidant agent with therapeutic properties in experimental liver disease. CeO₂NPs have been reported to act as a ROS and reactive nitrogen species (RNS) scavenger and to have multi-enzyme mimetic activity, including SOD activity (deprotionation of superoxide anion into oxygen and hydrogen peroxide), catalase activity (conversion of hydrogen peroxide into oxygen and water), and peroxidase activity (reducing hydrogen peroxide into hydroxyl radicals). Consequently, the beneficial effects of CeO₂NPs treatment have been reported in many different medical fields other than hepatology, including neurology, ophthalmology, cardiology, and oncology. Unlike other antioxidants, CeO₂NPs are only active at pathogenic levels of ROS, being inert and innocuous in healthy cells. In the current article, we review the potential of CeO₂NPs in several experimental models of liver disease and their safety as a therapeutic agent in humans as well. Full article

(This article belongs to the Special Issue Antioxidant Agents for the Prevention and Therapy of Oxidative Stress in Hepatic Diseases)

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