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Resveratrol ameliorates iron overload induced liver fibrosis in mice by regulating iron homeostasis.

ABSTRACT: This study is intended to explore the protective effects of resveratrol (RES) on iron overload-induced liver fibrosis and its mechanism. Iron dextran (50 mg/kg) was injected intraperitoneally in all groups except the control group. Mice in the L-RES, M-RES and H-RES groups were gavaged with RES solution at 25, 50 mg/kg and 100 mg/kg, respectively, 4 h before injection of iron dextran every day; mice in the deferoxamine (DFO) group were injected with DFO intraperitoneally (100 mg/kg); mice in the control group received isovolumetric saline. After seven weeks of RES administration, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) activities and liver hydroxyproline (Hyp) levels were reduced; the malondialdehyde (MDA) activities decreased and the levels of superoxide dismutase (SOD) and glutathione (GSH) were raised. Hematoxylin and eosin (H&E), Prussian, and Masson staining indicated that RES treatment could improve cell damage and reduce hepatic iron deposition and collagen deposition in iron-overload mice. The expression of Bcl-2 was increased, the expression levels of Bax and caspase-3 were decreased under RES treatment. Moreover, RES reduced the expression of hepcidin, ferritin (Ft), divalent metal transporter-1 (DMT-1), transferrin receptor-2 (TFR-2), and raised the expression of ferroprotein-1 (FPN-1). In conclusion, RES could ameliorate iron overload-induced liver fibrosis, and the potential mechanisms may be related to antioxidant, anti-inflammatory, anti-apoptotic, and more importantly, regulation of iron homeostasis by reducing iron uptake and increasing iron export.

SUBMITTER: Wang H

PROVIDER: S-EPMC9188311 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Resveratrol ameliorates iron overload induced liver fibrosis in mice by regulating iron homeostasis.

Wang Hua H Jiang Chuan C Yang Yakun Y Li Jinghan J Wang Yihan Y Wang Chaonan C Gao Yonggang Y

PeerJ 20220608

This study is intended to explore the protective effects of resveratrol (RES) on iron overload-induced liver fibrosis and its mechanism. Iron dextran (50 mg/kg) was injected intraperitoneally in all groups except the control group. Mice in the L-RES, M-RES and H-RES groups were gavaged with RES solution at 25, 50 mg/kg and 100 mg/kg, respectively, 4 h before injection of iron dextran every day; mice in the deferoxamine (DFO) group were injected with DFO intraperitoneally (100 mg/kg); mice in the ...[more]

PMID: 35698613

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Project description:Background & aimsIron overload disorders such as hereditary hemochromatosis and iron loading anemias are a common cause of morbidity from liver diseases and increase risk of hepatic fibrosis and hepatocellular carcinoma (HCC). Treatment options for iron-induced damage are limited, partly because there is lack of animal models of human disease. Therefore, we investigated the effect of iron overload in liver-specific β-catenin knockout mice (KO), which are susceptible to injury, fibrosis and tumorigenesis following chemical carcinogen exposure.MethodsIron overload diet was administered to KO and littermate control (CON) mice for various times. To ameliorate an oxidant-mediated component of tissue injury, N-Acetyl-L-(+)-cysteine (NAC) was added to drinking water of mice on iron overload diet.ResultsKO on iron diet (KO +Fe) exhibited remarkable inflammation, followed by steatosis, oxidative stress, fibrosis, regenerating nodules and occurrence of occasional HCC. Increased injury in KO +Fe was associated with activated protein kinase B (AKT), ERK, and NF-κB, along with reappearance of β-catenin and target gene Cyp2e1, which promoted lipid peroxidation and hepatic damage. Addition of NAC to drinking water protected KO +Fe from hepatic steatosis, injury and fibrosis, and prevented activation of AKT, ERK, NF-κB and reappearance of β-catenin.ConclusionsThe absence of hepatic β-catenin predisposes mice to hepatic injury and fibrosis following iron overload, which was reminiscent of hemochromatosis and associated with enhanced steatohepatitis and fibrosis. Disease progression was notably alleviated by antioxidant therapy, which supports its chemopreventive role in the management of chronic iron overload disorders.Lay summaryLack of animal models for iron overload disorders makes it hard to study the disease process for improving therapies. Feeding high iron diet to mice that lack the β-catenin gene in liver cells led to increased inflammation followed by fat accumulation, cell death and wound healing that mimicked human disease. Administration of an antioxidant prevented hepatic injury in this model.

Project description:BackgroundThe polyphenol resveratrol has anti-inflammatory effects in various cells, tissues, animals and human settings of low-grade inflammation. Psoriasis is a disease of both localized and systemic low-grade inflammation. The Sirtuin1 enzyme thought to mediate the effects of resveratrol is present in skin and resveratrol is known to down regulate NF-κB; an important contributor in the development of psoriasis. Consequently we investigated whether resveratrol has an effect on an Imiquimod induced psoriasis-like skin inflammation in mice and sought to identify candidate genes, pathways and interleukins mediating the effects.MethodsThe study consisted of three treatment groups: A control group, an Imiquimod group and an Imiquimod+resveratrol group. Psoriasis severity was assessed using elements of the Psoriasis Area Severity Index, skin thickness measurements, and histological examination. We performed an RNA microarray from lesional skin and afterwards Ingenuity pathway analysis to identify affected signalling pathways. Our microarray was compared to a previously deposited microarray to determine if gene changes were psoriasis-like, and to a human microarray to determine if findings could be relevant in a human setting.ResultsImiquimod treatment induced a psoriasis-like skin inflammation. Resveratrol significantly diminished the severity of the psoriasis-like skin inflammation. The RNA microarray revealed a psoriasis-like gene expression-profile in the Imiquimod treated group, and highlighted several resveratrol dependent changes in relevant genes, such as increased expression of genes associated with retinoic acid stimulation and reduced expression of genes involved in IL-17 dependent pathways. Quantitative PCR confirmed a resveratrol dependent decrease in mRNA levels of IL-17A and IL-19; both central in developing psoriasis.ConclusionsResveratrol ameliorates psoriasis, and changes expression of retinoic acid stimulated genes, IL-17 signalling pathways, IL-17A and IL-19 mRNA levels in a beneficial manner, which suggests resveratrol, might have a role in the treatment of psoriasis and should be explored further in a human setting.

Dataset Information

Resveratrol ameliorates iron overload induced liver fibrosis in mice by regulating iron homeostasis.

Publications

Resveratrol ameliorates iron overload induced liver fibrosis in mice by regulating iron homeostasis.

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