The Protective Effect of Grape-Seed Proanthocyanidin Extract on Oxidative Damage Induced by Zearalenone in Kunming Mice Liver

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Abstract

Although grape-seed proanthocyanidin extract (GSPE) demonstrates strong anti-oxidant activity, little research has been done to clearly reveal the protective effects on the hepatotoxicity caused by zearalenone (ZEN). This study is to explore the protective effect of GSPE on ZEN-induced oxidative damage of liver in Kunming mice and the possible protective molecular mechanism of GSPE. The results indicated that GSPE could greatly reduce the ZEN-induced increase of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. GSPE also significantly decreased the content of MDA but enhanced the activities of antioxidant enzymes SOD and GSH-Px. The analysis indicated that ZEN decreased both mRNA expression levels and protein expression levels of nuclear erythroid2-related factor2 (Nrf2). Nrf2 is considered to be an essential antioxidative transcription factor, as downstream GSH-Px, γ-glutamyl cysteine synthetase (γ-GCS), hemeoxygenase-1 (HO-1), and quinone oxidoreductase 1 (NQO1) decreased simultaneously, whereas the pre-administration of GSPE groups was shown to elevate these expressions. The results indicated that GSPE exerted a protective effect on ZEN-induced hepatic injury and the mechanism might be related to the activation of the Nrf2/ARE signaling pathway.

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Most cited references 41

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Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation.

Makoto Kobayashi, Masayuki Yamamoto (2005)

Several years have passed since NF-E2-related factor 2 (Nrf2) was demonstrated to regulate the induction of genes encoding antioxidant proteins and phase 2 detoxifying enzymes. Following a number of studies, it was realized that Nrf2 is a key factor for cytoprotection in various aspects, such as anticarcinogenicity, neuroprotection, antiinflammatory response, and so forth. These widespread functions of Nrf2 spring from the coordinated actions of various categories of target genes. The activation mechanism of Nrf2 has been studied extensively. Under normal conditions, Nrf2 localizes in the cytoplasm where it interacts with the actin binding protein, Kelch-like ECH associating protein 1 (Keap1), and is rapidly degraded by the ubiquitin-proteasome pathway. Signals from reactive oxygen species or electrophilic insults target the Nrf2-Keap1 complex, dissociating Nrf2 from Keap1. Stabilized Nrf2 then translocates to the nuclei and transactivates its target genes. Interestingly, Keap1 is now assumed to be a substrate-specific adaptor of Cul3-based E3 ubiquitin ligase. Direct participation of Keap1 in the ubiquitination and degradation of Nrf2 is plausible. The Nrf2-Keap1 system is present not only in mammals, but in fish, suggesting that its roles in cellular defense are conserved throughout evolution among vertebrates. This review article recounts recent knowledge of the Nrf2-Keap1 system, focusing especially on the molecular mechanism of Nrf2 regulation.

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Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter.

Mi-Kyoung Kwak, Ken Itoh, Masayuki Yamamoto … (2002)

Induction of phase 2 enzymes, which neutralize reactive electrophiles and act as indirect antioxidants, is an important mechanism for protection against carcinogenesis. The transcription factor Nrf2, which binds to the antioxidant response element (ARE) found in the upstream regulatory region of many phase 2 genes, is essential for the induction of these enzymes. We have investigated the effect of the potent enzyme inducer and anticarcinogen 3H-1,2-dithiole-3-thione (D3T) on the fate of Nrf2 in murine keratinocytes. Both total and nuclear Nrf2 levels increased rapidly and persistently after treatment with D3T but could be blocked by cotreatment with cycloheximide. Nrf2 mRNA levels increased approximately 2-fold 6 h after D3T treatment. To examine the transcriptional activation of Nrf2 by D3T, the proximal region (1 kb) of the nrf2 promoter was isolated. Deletion and mutagenesis analyses demonstrated that nrf2 promoter-luciferase reporter activity was enhanced by treatment with D3T and that ARE-like sequences were required for this activation. Gel shift assays with nuclear extracts from PE cells indicated that common factors bind to typical AREs and the ARE-like sequences of the nrf2 promoter. Direct binding of Nrf2 to its own promoter was demonstrated by chromatin immunoprecipitation assay. Overexpression of Nrf2 increased the activity of the nrf2 promoter-luciferase reporter, while expression of mutant Nrf2 protein repressed activity. Thus, Nrf2 appears to autoregulate its own expression through an ARE-like element located in the proximal region of its promoter, leading to persistent nuclear accumulation of Nrf2 and protracted induction of phase 2 genes in response to chemopreventive agents.

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Cytotoxicity, inhibition of DNA and protein syntheses and oxidative damage in cultured cells exposed to zearalenone.

H Bacha, W. Hassen, I Baudrimont … (2004)

Mycotoxins are toxic metabolites of various fungi commonly found in feed and foodstuff and can cause very serious health problems in animals as well as in humans. Zearalenone (ZEN), a mycotoxin produced by various Fusarium species has several adverse effects. Indeed, ZEN has strong estrogenic activity associated with hyperestrogenism and several physiological alterations of the reproductive tract. Moreover, ZEN was shown to be hepatotoxic, haematotoxic, immunotoxic and genotoxic. The exact mechanism of ZEN toxicity is not completely established. The observed strong estrogenic effect of ZEN resulting from its competition with 17beta-estradiol in the binding to estrogen receptors is generally considered to underline most toxic effects of ZEN, but estrogenic activity alone cannot explain the diverse and apparent adverse effects. The objective of the present study was to determine the involvement of other possible mechanisms in ZEN induced toxicity. Cytotoxicity, cell cycle perturbation, inhibition of protein and DNA synthesis as well as the presumed later marker of oxidative stress, malondialdehyde, were monitored in Vero and Caco-2 cells exposed to ZEN. Our results showed that ZEN reduces cell viability correlated to cell cycle perturbation, inhibits protein and DNA syntheses and increases MDA formation in both cell lines in concentration-dependant manner. We assumed that cytotoxicity and oxidative damage are additional mechanisms of ZEN mediated toxicity.

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Author and article information

Contributors

Maurizio Battino: Role: Academic Editor

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 25 May 2016

Publication date Collection: June 2016

Volume: 17

Issue: 6

Electronic Location Identifier: 808

Affiliations

[1 ]Key Laboratory of Zoonosis of Liaoning Province, College of Animal Science & Veterinary Medicine, Shenyang Agricultural University, Shenyang 110866, China; longjlau@ 123456126.com (M.L.); yangshuhua0001@ 123456126.com (S.-H.Y.); myworld_a4@ 123456126.com (J.-X.H.); lipeng79625@ 123456163.com (P.L.); sihuo12345@ 123456sohu.com (Y.Z.); DongS_FOCUS@ 123456163.com (S.D.); xinliang@ 123456syau.edu.cn (X.C.); guoniuniu163@ 123456163.com (J.G.)

[2 ]College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China

Author notes

[* ]Correspondence: junwang2004@ 123456126.com (J.W.); hejianbin69@ 123456163.com (J.-B.H.); Tel./Fax: +86-431-8453-2812 (J.W.); +86-24-8848-7156 (J.-B.H.)

[†]

These authors contributed equally to this study.

Article

Publisher ID: ijms-17-00808

DOI: 10.3390/ijms17060808

PMC ID: 4926342

PubMed ID: 27231898

SO-VID: 67b97add-1bb1-4920-aa1f-95d8e274a391

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This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

The Protective Effect of Grape-Seed Proanthocyanidin Extract on Oxidative Damage Induced by Zearalenone in Kunming Mice Liver

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Abstract

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Most cited references 41

Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation.

Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter.

Cytotoxicity, inhibition of DNA and protein syntheses and oxidative damage in cultured cells exposed to zearalenone.

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