Upregulation of Carbonyl Reductase 1 by Nrf2 as a Potential Therapeutic Intervention for Ischemia/Reperfusion Injury during Liver Transplantation

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Abstract

Currently, liver transplantation is the only available remedy for patients with end-stage liver disease. Conservation of transplanted liver graft is the most important issue as it directly related to patient survival. Carbonyl reductase 1 (CBR1) protects cells against oxidative stress and cell death by inactivating cellular membrane-derived lipid aldehydes. Ischemia-reperfusion (I/R) injury during living-donor liver transplantation is known to form reactive oxygen species. Thus, the objective of this study was to investigate whether CBR1 transcription might be increased during liver I/R injury and whether such increase might protect liver against I/R injury. Our results revealed that transcription factor Nrf2 could induce CBR1 transcription in liver of mice during I/R. Pre-treatment with sulforaphane, an activator of Nrf2, increased CBR1 expression, decreased liver enzymes such as aspartate aminotransferase and alanine transaminase, and reduced I/R-related pathological changes. Using oxygen-glucose deprivation and recovery model of human normal liver cell line, it was found that oxidative stress markers and lipid peroxidation products were significantly lowered in cells overexpressing CBR1. Conversely, CBR1 knockdown cells expressed elevated levels of oxidative stress proteins compared to the parental cell line. We also observed that Nrf2 and CBR1 were overexpressed during liver transplantation in clinical samples. These results suggest that CBR1 expression during liver I/R injury is regulated by transcription factor Nrf2. In addition, CBR1 can reduce free radicals and prevent lipid peroxidation. Taken together, CBR1 induction might be a therapeutic strategy for relieving liver I/R injury during liver transplantation.

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The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress.

Truyen Nguyen, Paul Nioi, Cecil B. Pickett (2009)

A major mechanism in the cellular defense against oxidative or electrophilic stress is activation of the Nrf2-antioxidant response element signaling pathway, which controls the expression of genes whose protein products are involved in the detoxication and elimination of reactive oxidants and electrophilic agents through conjugative reactions and by enhancing cellular antioxidant capacity. At the molecular level, however, the regulatory mechanisms involved in mediating Nrf2 activation are not fully understood. It is well established that Nrf2 activity is controlled, in part, by the cytosolic protein Keap1, but the nature of this pathway and the mechanisms by which Keap1 acts to repress Nrf2 activity remain to be fully characterized and are the topics of discussion in this minireview. In addition, a possible role of the Nrf2-antioxidant response element transcriptional pathway in neuroprotection will also be discussed.

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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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Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs.

Xiuwen Tang, Hongyan Wang, Longfang Fan … (2011)

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor regulating the expression of a battery of cytoprotective genes. Constitutive Nrf2 activation in many tumors enhances cell survival and resistance to anticancer drugs. Using a cell-based ARE-reporter assay we discovered that the flavonoid luteolin is a potent Nrf2 inhibitor. Luteolin inhibited ARE-driven gene expression redox-independently. In non-small-cell lung cancer A549 cells, which possess constitutively active Nrf2, luteolin elicited a dramatic reduction in Nrf2 at both the mRNA and the protein levels, leading to decreased Nrf2 binding to AREs, down-regulation of ARE-driven genes, and depletion of reduced glutathione. After transcription was blocked with actinomycin D, 1μM luteolin decreased the Nrf2 mRNA level by 34% in 30 min, indicating its role in accelerating Nrf2 mRNA turnover. At physiological concentrations, luteolin significantly sensitized A549 cells to the anticancer drugs oxaliplatin, bleomycin, and doxorubicin. However, knockdown of Nrf2 using siRNA essentially abolished the induced sensitivity by the flavonoid, implying the importance of inhibiting Nrf2 for its activity. Our study demonstrates that an Nrf2 inhibitor can enhance the responsiveness of cancer cells to chemotherapeutic drugs and indicates the potential application of luteolin as a natural sensitizer in chemotherapy. Copyright © 2011 Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Mol Cells

Journal ID (iso-abbrev): Mol. Cells

Journal ID (publisher-id): ksmcb

Title: Molecules and Cells

Publisher: Korean Society for Molecular and Cellular Biology

ISSN (Print): 1016-8478

ISSN (Electronic): 0219-1032

Publication date (Print): September 2019

Publication date (Electronic): 05 September 2019

Publication date PMC-release: 05 September 2019

Volume: 42

Issue: 9

Pages: 672-685

Affiliations

[1 ]Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea

[2 ]Department of Convergence Medicine, Asan Medical Institute of Convergence Science and Technology; and Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea

[3 ]Division of Transplantation, Department of Surgery and Asan-Minnesota Institute for Innovating Transplantation, University of Minnesota, Minneapolis, MN 55455, USA

[4 ]Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea

[5 ]Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka 584-8540, Japan

[6 ]Asan-Minnesota Institute for Innovating Transplantation, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea

Author notes

[* ]Correspondence: youngin83@ 123456naver.com (YIY); eunyoung.tak@ 123456amc.seoul.kr (ET)

[7]

These authors contributed equally to this work.

Author information

Jae Hyun Kwon https://orcid.org/0000-0001-8605-9350

Jooyoung Lee https://orcid.org/0000-0002-7938-8196

Jiye Kim https://orcid.org/0000-0002-5758-6810

Varvara A. Kirchner https://orcid.org/0000-0002-6949-9327

Yong Hwa Jo https://orcid.org/0000-0002-3957-3872

Takeshi Miura https://orcid.org/0000-0002-2433-211X

Nayoung Kim https://orcid.org/0000-0001-8598-0068

Gi-Won Song https://orcid.org/0000-0002-1581-7051

Shin Hwang https://orcid.org/0000-0002-9045-2531

Sung-Gyu Lee https://orcid.org/0000-0001-9161-3491

Young-In Yoon https://orcid.org/0000-0002-9308-0366

Eunyoung Tak https://orcid.org/0000-0002-2595-3639

Article

Publisher ID: molce-42-9-672

DOI: 10.14348/molcells.2019.0003

PMC ID: 6776159

PubMed ID: 31486328

SO-VID: 6d1bd9e3-0594-4e52-95bf-975829e03cad

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

History

Date received : 04 January 2019

Date revision received : 03 May 2019

Date accepted : 22 August 2019

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