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Oxidative Stress in Liver Diseases - 2nd Edition

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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 (20 November 2023) | Viewed by 25154

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Special Issue Editors

Prof. Dr. Greg Barritt

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Guest Editor

Medical Biochemistry, College of Medicine and Public Health, Flinders University, G.P.O. Box 2100 Adelaide, South Australia
Interests: non-alcoholic fatty liver disease; paracetamol toxicity; regulation of hepatocyte metabolism; liver ischemia-reperfusion injury; TRPM2 calcium channels; intracellular calcium signaling
Special Issues, Collections and Topics in MDPI journals

Dr. Eunus S. Ali

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Guest Editor

Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Interests: calcium signalling and lipid metabolism; hepatic nucleotide metabolism; liver IR injury; liver cancer; redox signaling; ROS metabolism in obesity and cancer; transporter and ion channel biology

Special Issue Information

Dear Colleagues,

The generation of reactive oxygen species (ROS) and subsequent oxidative stress play central roles in both acute and chronic liver diseases. These include drug toxicity, ischemia–reperfusion injury following liver surgery, alcoholic and nonalcoholic fatty liver disease, type 2 diabetes, hepatitis and other infections, and hepatocellular carcinoma. Of particular importance is the role of pathological fat accumulation in the generation of ROS in nonalcoholic steatohepatitis and in the promotion of hepatocellular carcinoma. Recent research has also highlighted the roles of intracellular calcium and calcium channels such as TRPM2 in the generation and actions of ROS in liver cells. Other current research has focused on pathways involved in the removal of ROS, including heme oxygenase-1, glutathione S-transferase A2 and the Nrf2 pathway, and interventions which inhibit the production and/or actions of ROS.

Volume 1 of the Special Issue “Oxidative Stress and Liver Disease” was recently published, with 15 original research articles and 6 reviews (https://www.mdpi.com/journal/antioxidants/special_issues/Oxidative_Stress_Liver). This first volume includes papers on the actions of established and new natural products and defined chemicals on ROS and liver disease, mechanisms by which known and novel chemicals interact with ROS-mediated pathways, and overviews of current knowledge of ROS and antioxidants in liver diseases. Papers published in the original Special Issue highlight the need for further research on mechanisms and specificity for interventions designed to reduce oxidative stress in liver disease. The great interest shown by liver and ROS researchers in the first Special Issue encouraged us to create Volume 2.

We invite you to submit your latest research findings or a review to Volume 2 of this Special Issue. We aim to bring together current knowledge of the mechanisms and pathways involved in the generation and action of ROS in the liver, as well as reports of potential pharmacological strategies for the reduction of liver injury induced by ROS. We welcome submissions on any of these areas, and would be particularly interested in research on: mechanisms and pathways involved in the actions of natural products which interact with ROS in the liver; the roles of lipids, paracetamol, intracellular calcium, and reperfusion following ischemia in the generation of ROS; mechanisms of ROS-induced hepatocyte injury, especially in the progression of hepatocellular carcinoma; the roles of heme oxygenase-1 and the Nrf2 pathway in protecting against ROS damage; and mechanisms involved in the actions of re-purposed drugs and natural products such as resveratrol, curcumin, and silymarin in strategies to reduce ROS-induced liver injury. In addition to papers on ROS and oxidative stress in human liver disease, we also welcome studies on other animals, fish, and birds. We believe that Volume 2 of this Special Issue will offer a snapshot of current knowledge on the role of ROS in liver disease that will not only include important current advances, but will be a worthwhile resource for postgraduates and other researchers new to the area wishing to gain a reliable benchmark of current knowledge in this field.

We look forward to your contribution, and would be very happy to discuss your suggestions.

Prof. Dr. Greg Barritt
Dr. Eunus S. Ali
Guest Editors

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Keywords

liver disease
fatty liver
lipid peroxidation
intracellular calcium
ischemia-reperfusion injury
natural products
pharmacological intervention

Published Papers (12 papers)

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Research

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36 pages, 16145 KiB

Open AccessArticle

Potential Hepatoprotective Effects of Chamaecyparis lawsoniana against Methotrexate-Induced Liver Injury: Integrated Phytochemical Profiling, Target Network Analysis, and Experimental Validation

by Eman Fikry, Raha Orfali, Shaimaa S. El-Sayed, Shagufta Perveen, Safina Ghafar, Azza M. El-Shafae, Maher M. El-Domiaty and Nora Tawfeek

Antioxidants 2023, 12(12), 2118; https://doi.org/10.3390/antiox12122118 - 14 Dec 2023

Viewed by 1247

Abstract

Methotrexate (MTX) therapy encounters significant limitations due to the significant concern of drug-induced liver injury (DILI), which poses a significant challenge to its usage. To mitigate the deleterious effects of MTX on hepatic function, researchers have explored plant sources to discover potential hepatoprotective agents. This study investigated the hepatoprotective effects of the ethanolic extract derived from the aerial parts of Chamaecyparis lawsoniana (CLAE) against DILI, specifically focusing on MTX-induced hepatotoxicity. UPLC-ESI-MS/MS was used to identify 61 compounds in CLAE, with 31 potential bioactive compounds determined through pharmacokinetic analysis. Network pharmacology analysis revealed 195 potential DILI targets for the bioactive compounds, including TP53, IL6, TNF, HSP90AA1, EGFR, IL1B, BCL2, and CASP3 as top targets. In vivo experiments conducted on rats with acute MTX-hepatotoxicity revealed that administering CLAE orally at 200 and 400 mg/kg/day for ten days dose-dependently improved liver function, attenuated hepatic oxidative stress, inflammation, and apoptosis, and reversed the disarrayed hepatic histological features induced by MTX. In general, the findings of the present study provide evidence in favor of the hepatoprotective capabilities of CLAE in DILI, thereby justifying the need for additional preclinical and clinical investigations. Full article

(This article belongs to the Special Issue Oxidative Stress in Liver Diseases - 2nd Edition)

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19 pages, 5689 KiB

Open AccessArticle

Sappanone A Alleviates the Severity of Carbon Tetrachloride-Induced Liver Fibrosis in Mice

by Jing Qi, Lanqian Li, Xueqing Yan, Wenxi Hua and Zixiong Zhou

Antioxidants 2023, 12(9), 1718; https://doi.org/10.3390/antiox12091718 - 04 Sep 2023

Viewed by 1307

Abstract

Liver fibrosis is a major challenge to global health because of its various complications, including cirrhosis and hepatocarcinoma, while no effective treatment is available for it. Sappanone A (SA) is a homoisoflavonoid extracted from the heartwood of Caesalpinia sappan Linn. with anti-inflammatory and antioxidant properties. However, the effects of SA on hepatic fibrosis remain unknown. This study aimed to investigate the protective effects of SA on carbon tetrachloride (CCl₄)-induced liver fibrosis in mice. To establish a liver fibrosis model, mice were treated intraperitoneally (i.p.) with CCl₄ for 4 weeks. SA (25, 50, and 100 mg/kg body weight) was i.p. injected every other day during the same period. Our data indicated that SA decreased liver injury, fibrotic responses, and inflammation due to CCl₄ exposure. Consistently, SA reduced oxidative stress and its-mediated hepatocyte death in fibrotic livers. Of note, SA could not directly affect the activation of hepatic stellate cells. Mechanistically, SA treatment lessened oxidative stress-triggered cell death in hepatocytes after CCl₄ exposure. SA down-regulated the expression of M1 macrophage polarization markers (CD86 and iNOS) and up-regulated the expression of M2 macrophage polarization markers (CD163, IL-10, and Arg1) in livers and macrophages. Meanwhile, SA induced the activation of peroxisome proliferator-activated receptor gamma (PPARγ). However, decreased inflammatory responses and the trend of M2 macrophage polarization provided by SA were substantially abolished by SR202 (a PPARγ inhibitor) treatment in macrophages. Additionally, SA treatment promoted fibrosis regression. Taken together, our findings revealed that treatment with SA alleviated CCl₄-induced fibrotic liver in mice through suppression of oxidative stress-mediated hepatocyte death and promotion of M2 macrophage polarization via PPARγ. Thus, SA might pave the way for a new hepatoprotective agent to treat liver fibrosis. Full article

(This article belongs to the Special Issue Oxidative Stress in Liver Diseases - 2nd Edition)

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17 pages, 8144 KiB

Open AccessArticle

Functional and Structural Insights into the Human PPARα/δ/γ Targeting Preferences of Anti-NASH Investigational Drugs, Lanifibranor, Seladelpar, and Elafibranor

by Shotaro Kamata, Akihiro Honda, Ryo Ishikawa, Makoto Akahane, Ayane Fujita, Chihiro Kaneko, Saeka Miyawaki, Yuki Habu, Yui Shiiyama, Kie Uchii, Yui Machida, Takuji Oyama and Isao Ishii

Antioxidants 2023, 12(8), 1523; https://doi.org/10.3390/antiox12081523 - 29 Jul 2023

Cited by 6 | Viewed by 1750

Abstract

No therapeutic drugs are currently available for nonalcoholic steatohepatitis (NASH) that progresses from nonalcoholic fatty liver via oxidative stress-involved pathways. Three cognate peroxisome proliferator-activated receptor (PPAR) subtypes (PPARα/δ/γ) are considered as attractive targets. Although lanifibranor (PPARα/δ/γ pan agonist) and saroglitazar (PPARα/γ dual agonist) are currently under investigation in clinical trials for NASH, the development of seladelpar (PPARδ-selective agonist), elafibranor (PPARα/δ dual agonist), and many other dual/pan agonists has been discontinued due to serious side effects or little/no efficacies. This study aimed to obtain functional and structural insights into the potency, efficacy, and selectivity against PPARα/δ/γ of three current and past anti-NASH investigational drugs: lanifibranor, seladelpar, and elafibranor. Ligand activities were evaluated by three assays to detect different facets of the PPAR activation: transactivation assay, coactivator recruitment assay, and thermal stability assay. Seven high-resolution cocrystal structures (namely, those of the PPARα/δ/γ-ligand-binding domain (LBD)–lanifibranor, PPARα/δ/γ-LBD–seladelpar, and PPARα-LBD–elafibranor) were obtained through X-ray diffraction analyses, six of which represent the first deposit in the Protein Data Bank. Lanifibranor and seladelpar were found to bind to different regions of the PPARα/δ/γ-ligand-binding pockets and activated all PPAR subtypes with different potencies and efficacies in the three assays. In contrast, elafibranor induced transactivation and coactivator recruitment (not thermal stability) of all PPAR subtypes, but the PPARδ/γ-LBD–elafibranor cocrystals were not obtained. These results illustrate the highly variable PPARα/δ/γ activation profiles and binding modes of these PPAR ligands that define their pharmacological actions. Full article

(This article belongs to the Special Issue Oxidative Stress in Liver Diseases - 2nd Edition)

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15 pages, 4130 KiB

Open AccessArticle

Low-Dose Acetylsalicylic Acid and Mitochondria-Targeted Antioxidant Mitoquinone Attenuate Non-Alcoholic Steatohepatitis in Mice

by Saadet Turkseven, Cristian Turato, Gianmarco Villano, Mariagrazia Ruvoletto, Maria Guido, Massimo Bolognesi, Patrizia Pontisso and Marco Di Pascoli

Antioxidants 2023, 12(4), 971; https://doi.org/10.3390/antiox12040971 - 21 Apr 2023

Cited by 2 | Viewed by 1477

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. NAFLD can evolve from simple fatty liver to non-alcoholic steatohepatitis (NASH), and ultimately, to cirrhosis. Inflammation and oxidative stress, promoted by mitochondrial dysfunction, play a crucial role in the onset and development of NASH. To date, no therapy has been approved for NAFLD and NASH. The aim of this study is to evaluate if the anti-inflammatory activity of acetylsalicylic acid (ASA) and the mitochondria-targeted antioxidant effect of mitoquinone could hinder the progression of non-alcoholic steatohepatitis. In mice, fatty liver was induced through the administration of a deficient in methionine and choline and rich in fat diet. Two experimental groups were treated orally with ASA or mitoquinone. Histopathologic evaluation of steatosis and inflammation was performed; the hepatic expression of genes associated with inflammation, oxidative stress, and fibrosis was evaluated; the protein expression of IL-10, cyclooxygenase 2, superoxide dismutase 1, and glutathione peroxidase 1 in the liver was analyzed; a quantitative analysis of 15-epi-lipoxin A4 in liver homogenates was performed. Mitoquinone and ASA significantly reduced liver steatosis and inflammation by decreasing the expression of TNFα, IL-6, Serpinb3, and cyclooxygenase 1 and 2 and restoring the anti-inflammatory IL-10. Treatment with mitoquinone and ASA increased the gene and protein expression of antioxidants, i.e., catalase, superoxide dismutase 1, and glutathione peroxidase 1, and decreased the expression of profibrogenic genes. ASA normalized the levels of 15-epi-Lipoxin A4. In mice fed with a deficient in methionine and choline and rich in fat diet, mitoquinone and ASA reduce steatosis and necroinflammation and may represent two effective novel strategies for the treatment of non-alcoholic steatohepatitis. Full article

(This article belongs to the Special Issue Oxidative Stress in Liver Diseases - 2nd Edition)

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18 pages, 7431 KiB

Open AccessArticle

Nuciferine Effectively Protects Mice against Acetaminophen-Induced Liver Injury

by Zixiong Zhou, Jing Qi, Yajiao Wu, Chutao Li, Wenqiang Bao, Xiaohuang Lin and An Zhu

Antioxidants 2023, 12(4), 949; https://doi.org/10.3390/antiox12040949 - 18 Apr 2023

Cited by 3 | Viewed by 1933

Abstract

Acetaminophen (APAP) overdose still poses a major clinical challenge and is a leading cause of acute liver injury (ALI). N-acetylcysteine (NAC) is the only approved antidote to treat APAP toxicity while NAC therapy can trigger side effects including severe vomiting and even shock. Thus, new insights in developing novel therapeutic drugs may pave the way for better treatment of APAP poisoning. Previous research has reported that nuciferine (Nuci) possesses anti-inflammatory and antioxidant properties. Therefore, the objective of this study was proposed to investigate the hepatoprotective effects of Nuci and explore its underlying mechanisms. Mice were intraperitoneally (i.p.) administered with APAP (300 mg/kg) and subsequently injected with Nuci (25, 50, and 100 mg/kg, i.p.) at 30 min after APAP overdose. Then, all mice were sacrificed at 12 h after APAP challenge for further analysis. Nuci-treated mice did not show any side effects and our results revealed that treating Nuci significantly attenuated APAP-induced ALI, as confirmed by histopathological examinations, biochemical analysis, and diminished hepatic oxidative stress and inflammation. The in silico prediction and mRNA-sequencing analysis were performed to explore the underlying mechanisms of Nuci. GO and KEGG enrichment of the predicted target proteins of Nuci includes reactive oxygen species, drug metabolism of cytochrome P450 (CYP450) enzymes, and autophagy. Furthermore, the mRNA-sequencing analyses indicated that Nuci can regulate glutathione metabolic processes and anti-inflammatory responses. Consistently, we found that Nuci increased the hepatic glutathione restoration but decreased APAP protein adducts in damaged livers. Western blot analysis further confirmed that Nuci effectively promoted hepatic autophagy in APAP-treated mice. However, Nuci could not affect the expression levels of the main CYP450 enzymes (CYP1A2, CYP2E1, and CYP3A11). These results demonstrated that Nuci may be a potential therapeutic drug for APAP-induced ALI via amelioration of the inflammatory response and oxidative stress, regulation of APAP metabolism, and activation of autophagy. Full article

(This article belongs to the Special Issue Oxidative Stress in Liver Diseases - 2nd Edition)

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14 pages, 2694 KiB

Open AccessArticle

Acute Kidney Injury Induces Oxidative Stress and Hepatic Lipid Accumulation through AMPK Signaling Pathway

by Kathy K. W. Au-Yeung, Yue Shang, Charith U. B. Wijerathne, Susara Madduma Hewage, Yaw L. Siow and Karmin O

Antioxidants 2023, 12(4), 883; https://doi.org/10.3390/antiox12040883 - 05 Apr 2023

Cited by 4 | Viewed by 2119

Abstract

Acute kidney injury (AKI) often impairs the function of other organs leading to distant organ injury. The liver is the major organ that regulates metabolism and lipid homeostasis in the body. It has been reported that AKI causes liver injury with increased oxidative stress, inflammatory response and steatosis. In the present study, we investigated the mechanisms by which ischemia-reperfusion-induced AKI caused hepatic lipid accumulation. Kidney ischemia (45 min)-reperfusion (24 h) led to a significant increase in plasma creatinine and transaminase in Sprague Dawley rats, indicating kidney and liver injury. Histological and biochemical analyses revealed hepatic lipid accumulation with a significant elevation of triglyceride and cholesterol levels in the liver. This was accompanied by a decreased AMP-activated protein kinase (AMPK) phosphorylation, indicating the reduced activation of AMPK, which is an energy sensor that regulates lipid metabolism. The expression of AMPK-regulated genes that were responsible for fatty acid oxidation (CPTIα, ACOX) was significantly decreased, while the expression of lipogenesis genes (SREPB-1c, ACC1) was significantly elevated. The oxidative stress biomarker malondialdehyde was elevated in the plasma and liver. Incubation of HepG2 cells with an oxidative stress inducer hydrogen peroxide inhibited AMPK phosphorylation and caused cellular lipid accumulation. This was accompanied by decreased expression of genes responsible for fatty acid oxidation and increased expression of genes responsible for lipogenesis. These results suggest that AKI elicits hepatic lipid accumulation through decreased fatty acid metabolism and increased lipogenesis. Oxidative stress may contribute, in part, to the downregulation of the AMPK signaling pathway leading to hepatic lipid accumulation and injury. Full article

(This article belongs to the Special Issue Oxidative Stress in Liver Diseases - 2nd Edition)

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17 pages, 3558 KiB

Open AccessArticle

Cranberry Proanthocyanidins as a Therapeutic Strategy to Curb Metabolic Syndrome and Fatty Liver-Associated Disorders

by Francis Feldman, Mireille Koudoufio, Ramy El-Jalbout, Mathilde Foisy Sauvé, Lena Ahmarani, Alain Théophile Sané, Nour-El-Houda Ould-Chikh, Thierry N’Timbane, Natalie Patey, Yves Desjardins, Alain Stintzi, Schohraya Spahis and Emile Levy

Antioxidants 2023, 12(1), 90; https://doi.org/10.3390/antiox12010090 - 30 Dec 2022

Cited by 4 | Viewed by 1953

Abstract

While the prevalence of metabolic syndrome (MetS) is steadily increasing worldwide, no optimal pharmacotherapy is readily available to address its multifaceted risk factors and halt its complications. This growing challenge mandates the development of other future curative directions. The purpose of the present study is to investigate the efficacy of cranberry proanthocyanidins (PACs) in improving MetS pathological conditions and liver complications; C57BL/6J mice were fed either a standard chow or a high fat/high sucrose (HFHS) diet with and without PACs (200 mg/kg), delivered by daily gavage for 12 weeks. Our results show that PACs lowered HFHS-induced obesity, insulin resistance, and hyperlipidemia. In conjunction, PACs lessened circulatory markers of oxidative stress (OxS) and inflammation. Similarly, the anti-oxidative and anti-inflammatory capacities of PACs were noted in the liver in association with improved hepatic steatosis. Inhibition of lipogenesis and stimulation of beta-oxidation could account for PACs-mediated decline of fatty liver as evidenced not only by the expression of rate-limiting enzymes but also by the status of AMPKα (the key sensor of cellular energy) and the powerful transcription factors (PPARα, PGC1α, SREBP1c, ChREBP). Likewise, treatment with PACs resulted in the downregulation of critical enzymes of liver gluconeogenesis, a process contributing to increased rates of glucose production in type 2 diabetes. Our findings demonstrate that PACs prevented obesity and improved insulin resistance likely via suppression of OxS and inflammation while diminishing hyperlipidemia and fatty liver disease, as clear evidence for their strength of fighting the cluster of MetS abnormalities. Full article

(This article belongs to the Special Issue Oxidative Stress in Liver Diseases - 2nd Edition)

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15 pages, 2686 KiB

Open AccessArticle

Bacillus subtilis-Fermented Amomum xanthioides Ameliorates Metabolic-Syndrome-Like Pathological Conditions in Long-Term HFHFD-Fed Mice

by Jing-Hua Wang, Seung-Ju Hwang, Kwang-Soo Shin, Dong-Woo Lim and Chang-Gue Son

Antioxidants 2022, 11(11), 2254; https://doi.org/10.3390/antiox11112254 - 15 Nov 2022

Cited by 3 | Viewed by 1962

Abstract

In modern society, numerous metabolic disorders are widespread globally. The present study aimed to demonstrate whether Bacillus subtilis-fermented Amomum xanthioides (BSAX) exerts anti-metabolic disturbance effects compared with the ethyl acetate fraction of Amomum xanthioides (EFAX), a previously verified functional fraction. Mice fed with a high-fat, high-fructose diet (HFHFD) for 10 wk presented a typical model of metabolic dysfunction, and BSAX significantly attenuated a string of metabolic-syndrome-related pathological parameters, such as body, fat, organ mass, lipid markers (TGs, TC, free fatty acids), and glucose metabolism (glucose, insulin), without influencing appetite. Further, BSAX markedly lowered malondialdehyde (MDA) and ROS in the blood and restored antioxidative parameters (SOD, GSH, and CAT in liver tissue, and total bilirubin in serum) by elevating Nrf2 and HO-1. Moreover, BSAX noticeably restored gut microbiota diversity and normalized lipid-metabolism-associated proteins, including SREBP-1, p-AMPK, and PPAR-α. Generally, most metabolic parameters were improved by BSAX to a greater extent than EFAX, except for liver weight and hepatic TC. In conclusion, BSAX alleviates metabolic dysfunction by enhancing lipid metabolism and antioxidative capacity and is more effective than EFAX. Therefore, the application of high-yield, effective BSAX might be a promising approach for curing and preventing metabolic disorders. Full article

(This article belongs to the Special Issue Oxidative Stress in Liver Diseases - 2nd Edition)

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26 pages, 8036 KiB

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Stress-Induced Premature Senescence Related to Oxidative Stress in the Developmental Programming of Nonalcoholic Fatty Liver Disease in a Rat Model of Intrauterine Growth Restriction

by Basile Keshavjee, Valentine Lambelet, Hanna Coppola, David Viertl, John O. Prior, Laurent Kappeler, Jean-Baptiste Armengaud, Jean-Pierre Chouraqui, Hassib Chehade, Paul-Emmanuel Vanderriele, Manon Allouche, Anne Balsiger, Alexandre Sarre, Anne-Christine Peyter, Umberto Simeoni and Catherine Yzydorczyk

Antioxidants 2022, 11(9), 1695; https://doi.org/10.3390/antiox11091695 - 29 Aug 2022

Cited by 5 | Viewed by 2783

Abstract

Metabolic syndrome (MetS) refers to cardiometabolic risk factors, such as visceral obesity, dyslipidemia, hyperglycemia/insulin resistance, arterial hypertension and non-alcoholic fatty liver disease (NAFLD). Individuals born after intrauterine growth restriction (IUGR) are particularly at risk of developing metabolic/hepatic disorders later in life. Oxidative stress and cellular senescence have been associated with MetS and are observed in infants born following IUGR. However, whether these mechanisms could be particularly associated with the development of NAFLD in these individuals is still unknown. IUGR was induced in rats by a maternal low-protein diet during gestation versus. a control (CTRL) diet. In six-month-old offspring, we observed an increased visceral fat mass, glucose intolerance, and hepatic alterations (increased transaminase levels, triglyceride and neutral lipid deposit) in male rats with induced IUGR compared with the CTRL males; no differences were found in females. In IUGR male livers, we identified some markers of stress-induced premature senescence (SIPS) (lipofuscin deposit, increased protein expression of p21^WAF, p16^INK4a and Acp53, but decreased pRb/Rb ratio, foxo-1 and sirtuin-1 protein and mRNA expression) associated with oxidative stress (higher superoxide anion levels, DNA damages, decreased Cu/Zn SOD, increased catalase protein expression, increased nfe2 and decreased keap1 mRNA expression). Impaired lipogenesis pathways (decreased pAMPK/AMPK ratio, increased pAKT/AKT ratio, SREBP1 and PPARγ protein expression) were also observed in IUGR male livers. At birth, no differences were observed in liver histology, markers of SIPS and oxidative stress between CTRL and IUGR males. These data demonstrate that the livers of IUGR males at adulthood display SIPS and impaired liver structure and function related to oxidative stress and allow the identification of specific therapeutic strategies to limit or prevent adverse consequences of IUGR, particularly metabolic and hepatic disorders. Full article

(This article belongs to the Special Issue Oxidative Stress in Liver Diseases - 2nd Edition)

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18 pages, 8968 KiB

Open AccessArticle

Paeonol Attenuates Hepatic Ischemia/Reperfusion Injury by Modulating the Nrf2/HO-1 and TLR4/MYD88/NF-κB Signaling Pathways

by Mohamed A. Morsy, Yasmine F. Ibrahim, Sara Mohamed Naguib Abdel Hafez, Nagwa M. Zenhom, Anroop B. Nair, Katharigatta N. Venugopala, Pottathil Shinu and Seham A. Abdel-Gaber

Antioxidants 2022, 11(9), 1687; https://doi.org/10.3390/antiox11091687 - 29 Aug 2022

Cited by 6 | Viewed by 1993

Abstract

Hepatic ischemia/reperfusion (HIR) is the most common type of liver injury following several clinical situations. Modulating oxidative stress and inflammation by Nrf2/HO-1 and TLR4/MYD88/NF-κB pathways, respectively, is involved in alleviating HIR injury. Paeonol is a natural phenolic compound that demonstrates significant antioxidant and anti-inflammatory effects. The present study explored the possible protective effect of paeonol against HIR injury and investigated its possible molecular mechanisms in rats. Rats were randomly divided into four groups: sham-operated control, paeonol-treated sham-operated control, HIR untreated, and HIR paeonol-treated groups. The results confirmed that hepatic injury was significantly aggravated biochemically by elevated serum levels of alanine transaminase and aspartate transaminase, as well as by histopathological alterations, while paeonol reduced the increase in transaminases and alleviated pathological changes induced by HIR. Additionally, paeonol inhibited the HIR-induced oxidative stress in hepatic tissues by decreasing the upraised levels of malondialdehyde and nitric oxide and enhancing the suppressed levels of reduced glutathione and superoxide dismutase activity. Furthermore, paeonol activated the protective antioxidative Nrf2/HO-1 pathway. The protective effect of paeonol was associated with inhibiting the expression of the inflammatory key mediators TLR4, MYD88, NF-κB, and TNF-α. Finally, paeonol inhibited the increased mRNA levels of the pro-apoptotic marker Bax and enhanced the reduced mRNA levels of the anti-apoptotic marker Bcl-2. Taken together, our results proved for the first time that paeonol could protect against HIR injury by inhibiting oxidative stress, inflammation, and apoptosis. Full article

(This article belongs to the Special Issue Oxidative Stress in Liver Diseases - 2nd Edition)

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24 pages, 4331 KiB

Open AccessArticle

Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen

by Rubén Rodríguez-Agudo, Naroa Goikoetxea-Usandizaga, Marina Serrano-Maciá, Pablo Fernández-Tussy, David Fernández-Ramos, Sofía Lachiondo-Ortega, Irene González-Recio, Clàudia Gil-Pitarch, María Mercado-Gómez, Laura Morán, Maider Bizkarguenaga, Fernando Lopitz-Otsoa, Petar Petrov, Miren Bravo, Sebastiaan Martijn Van Liempd, Juan Manuel Falcon-Perez, Amaia Zabala-Letona, Arkaitz Carracedo, Jose Vicente Castell, Ramiro Jover, Luis Alfonso Martínez-Cruz, Teresa Cardoso Delgado, Francisco Javier Cubero, María Isabel Lucena, Raúl Jesús Andrade, Jon Mabe, Jorge Simón and María Luz Martínez-Chantar Show full author list Hide full author list

Antioxidants 2022, 11(5), 897; https://doi.org/10.3390/antiox11050897 - 30 Apr 2022

Cited by 3 | Viewed by 4154

Abstract

Drug-induced liver injury (DILI) development is commonly associated with acetaminophen (APAP) overdose, where glutathione scavenging leads to mitochondrial dysfunction and hepatocyte death. DILI is a severe disorder without effective late-stage treatment, since N-acetyl cysteine must be administered 8 h after overdose to be efficient. Ammonia homeostasis is altered during liver diseases and, during DILI, it is accompanied by decreased glycine N-methyltransferase (GNMT) expression and S-adenosylmethionine (AdoMet) levels that suggest a reduced methionine cycle. Anti-miR-873-5p treatment prevents cell death in primary hepatocytes and the appearance of necrotic areas in liver from APAP-administered mice. In our study, we demonstrate a GNMT and methionine cycle activity restoration by the anti-miR-873-5p that reduces mitochondrial dysfunction and oxidative stress. The lack of hyperammoniemia caused by the therapy results in a decreased urea cycle, enhancing the synthesis of polyamines from ornithine and AdoMet and thus impacting the observed recovery of mitochondria and hepatocyte proliferation for regeneration. In summary, anti-miR-873-5p appears to be an effective therapy against APAP-induced liver injury, where the restoration of GNMT and the methionine cycle may prevent mitochondrial dysfunction while activating hepatocyte proliferative response. Full article

(This article belongs to the Special Issue Oxidative Stress in Liver Diseases - 2nd Edition)

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Review

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22 pages, 1406 KiB

Open AccessReview

Hepatoprotective Effects of Flavonoids against Benzo[a]Pyrene-Induced Oxidative Liver Damage along Its Metabolic Pathways

by Min Kim, Seung-Cheol Jee and Jung-Suk Sung

Antioxidants 2024, 13(2), 180; https://doi.org/10.3390/antiox13020180 - 31 Jan 2024

Viewed by 970

Abstract

Benzo[a]pyrene (B[a]P), a highly carcinogenic polycyclic aromatic hydrocarbon primarily formed during incomplete organic matter combustion, undergoes a series of hepatic metabolic reactions once absorbed into the body. B[a]P contributes to liver damage, ranging from molecular DNA damage to the onset and progression of various diseases, including cancer. Specifically, B[a]P induces oxidative stress via reactive oxygen species generation within cells. Consequently, more research has focused on exploring the underlying mechanisms of B[a]P-induced oxidative stress and potential strategies to counter its hepatic toxicity. Flavonoids, natural compounds abundant in plants and renowned for their antioxidant properties, possess the ability to neutralize the adverse effects of free radicals effectively. Although extensive research has investigated the antioxidant effects of flavonoids, limited research has delved into their potential in regulating B[a]P metabolism to alleviate oxidative stress. This review aims to consolidate current knowledge on B[a]P-induced liver oxidative stress and examines the role of flavonoids in mitigating its toxicity. Full article

(This article belongs to the Special Issue Oxidative Stress in Liver Diseases - 2nd Edition)

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Oxidative Stress in Liver Diseases - 2nd Edition

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