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      A Bibliometric Review of the Keap1/Nrf2 Pathway and its Related Antioxidant Compounds

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          Abstract

          Nrf2 is a master transcriptional regulator of antioxidant and cytoprotective pathways. Currently in its third decade, research on Nrf2 has expanded to encompass not only basic but also clinical studies. In the present bibliometric review, we employed the VOSviewer tool to describe the existing Nrf2 literature landscape. As of July 2019, 11,931 papers on Nrf2 were listed in the “Web of Science” database, with more than 1000 new papers published each year. As expected, terms related to oxidative stress and antioxidant molecules occur very often in the Nrf2 literature throughout the years. Interestingly, there is also a gradual increase in the occurrence of terms related to diseases or to natural compounds, the most prominent being sulforaphane, curcumin, and resveratrol that modulate the Nrf2 pathway. Going beyond molecular biology/biochemistry and related fields, Nrf2 research has begun to spread into more clinical areas like endocrinology/metabolism, cardiology, and nephrology, likely reflecting an increased interest in clinical applications of Nrf2 pathway activators. China has become the most prolific producer of Nrf2 papers the last five years followed by the USA and Japan, a reverse pattern compared to the past. In conclusion, Nrf2 is the subject of a globally active research field that keeps growing and extends from bench to bedside.

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          Most cited references26

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          Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region.

          Hypersensitive site 2 located in the beta-globin locus control region confers high levels of expression to the genes of the beta-globin cluster. A tandem repeat of the consensus sequence for the transcription factors AP1 and NF-E2 (activating protein 1 and nuclear factor erythroid 2, respectively) is present within hypersensitive site 2 and is absolutely required for strong enhancer activity. This sequence binds, in vitro and in vivo, to ubiquitous proteins of the AP1 family and to the recently cloned erythroid-specific transcription factor NF-E2. Using the tandem repeat as a recognition site probe to screen a lambda gt11 cDNA expression library from K562 cells, we isolated several DNA binding proteins. Here, we report the characterization of one of the clones isolated. The gene, which we named Nrf2 (NF-E2-related factor 2), is encoded within a 2.2-kb transcript and predicts a 66-kDa protein with a basic leucine zipper DNA binding domain highly homologous to that of NF-E2. Although Nrf2 is expressed ubiquitously, a role of this protein in mediating enhancer activity of hypersensitive site 2 in erythroid cells cannot be excluded. In this respect, Nrf2 contains a powerful acidic activation domain that may participate in the transcriptional stimulation of beta-globin genes.
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            Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism.

            The major obstacle in cancer treatment is the resistance of cancer cells to therapies. Nrf2 is a transcription factor that regulates a cellular defense response and is ubiquitously expressed at low basal levels in normal tissues due to Keap1-dependent ubiquitination and proteasomal degradation. Recently, Nrf2 has emerged as an important contributor to chemoresistance. High constitutive expression of Nrf2 was found in many types of cancers, creating an environment conducive for cancer cell survival. Here, we report the identification of brusatol as a unique inhibitor of the Nrf2 pathway that sensitizes a broad spectrum of cancer cells and A549 xenografts to cisplatin and other chemotherapeutic drugs. Mechanistically, brusatol selectively reduces the protein level of Nrf2 through enhanced ubiquitination and degradation of Nrf2. Consequently, expression of Nrf2-downstream genes is reduced and the Nrf2-dependent protective response is suppressed. In A549 xenografts, brusatol and cisplatin cotreatment induced apoptosis, reduced cell proliferation, and inhibited tumor growth more substantially when compared with cisplatin treatment alone. Additionally, A549-K xenografts, in which Nrf2 is expressed at very low levels due to ectopic expression of Keap1, do not respond to brusatol treatment, demonstrating that brusatol-mediated sensitization to cisplatin is Nrf2 dependent. Moreover, a decrease in drug detoxification and impairment in drug removal may be the primary mechanisms by which brusatol enhances the efficacy of chemotherapeutic drugs. Taken together, these results clearly demonstrate the effectiveness of using brusatol to combat chemoresistance and suggest that brusatol can be developed into an adjuvant chemotherapeutic drug.
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              Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway.

              The cap'n'collar (CNC) bZIP transcription factor Nrf2 controls expression of genes for antioxidant enzymes, metal-binding proteins, drug-metabolising enzymes, drug transporters, and molecular chaperones. Many chemicals that protect against carcinogenesis induce Nrf2-target genes. These compounds are all thiol-reactive and stimulate an adaptive response to redox stress in cells. Such agents induce the expression of genes that posses an antioxidant response element (ARE) in their regulatory regions. Under normal homeostatic conditions, Nrf2 activity is restricted through a Keap1-dependent ubiquitylation by Cul3-Rbx1, which targets the CNC-bZIP transcription factor for proteasomal degradation. However, as the substrate adaptor function of Keap1 is redox-sensitive, Nrf2 protein evades ubiquitylation by Cul3-Rbx1 when cells are treated with chemopreventive agents. As a consequence, Nrf2 accumulates in the nucleus where it heterodimerizes with small Maf proteins and transactivates genes regulated through an ARE. In this review, we describe synthetic compounds and phytochemicals from edible plants that induce Nrf2-target genes. We also discuss evidence for the existence of different classes of ARE (a 16-bp 5'-TMAnnRTGABnnnGCR-3' versus an 11-bp 5'-RTGABnnnGCR-3', with or without the embedded activator protein 1-binding site 5'-TGASTCA-3'), species differences in the ARE-gene battery, and the identity of critical Cys residues in Keap1 required for de-repression of Nrf2 by chemopreventive agents.
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                Author and article information

                Journal
                Antioxidants (Basel)
                Antioxidants (Basel)
                antioxidants
                Antioxidants
                MDPI
                2076-3921
                01 September 2019
                September 2019
                : 8
                : 9
                : 353
                Affiliations
                [1 ]Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital and University of Lausanne, SA08/02/250, Ave de la Sallaz 8, CH-1011 Lausanne, Switzerland
                [2 ]Division of Endocrinology, Department of Internal Medicine, School of Medicine, University of Patras, 265 04 Patras, Greece
                Author notes
                [* ]Correspondence: gerasimos.sykiotis@ 123456chuv.ch ; Tel.: +41-21-314-06-06; Fax: +41-21-314-80-31
                [†]

                Co-first authors.

                Author information
                https://orcid.org/0000-0002-6139-6067
                Article
                antioxidants-08-00353
                10.3390/antiox8090353
                6769514
                31480567
                2794fff1-52c7-4dc0-a89f-7df33fc07f70
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. 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/).

                History
                : 11 July 2019
                : 23 August 2019
                Categories
                Review

                nrf2,keap1,bibliography,sulforaphane,natural product,antioxidant,cytoprotection

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