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      Mechanisms of Nrf2/Keap1-Dependent Phase II Cytoprotective and Detoxifying Gene Expression and Potential Cellular Targets of Chemopreventive Isothiocyanates

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          Abstract

          Isothiocyanates (ITCs) are abundantly found in cruciferous vegetables. Epidemiological studies suggest that chronic consumption of cruciferous vegetables can lower the overall risk of cancer. Natural ITCs are key chemopreventive ingredients of cruciferous vegetables, and one of the prime chemopreventive mechanisms of natural isothiocyanates is the induction of Nrf2/ARE-dependent gene expression that plays a critical role in cellular defense against electrophiles and reactive oxygen species. In the present review, we first discuss the underlying mechanisms how natural ITCs affect the intracellular signaling kinase cascades to regulate the Keap1/Nrf2 activities, thereby inducing phase II cytoprotective and detoxifying enzymes. We also discuss the potential cellular protein targets to which natural ITCs are directly conjugated and how these events aid in the chemopreventive effects of natural ITCs. Finally, we discuss the posttranslational modifications of Keap1 and nucleocytoplasmic trafficking of Nrf2 in response to electrophiles and oxidants.

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          Most cited references38

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          Molecular mechanisms of Nrf2-mediated antioxidant response.

          Nrf2 is the key transcription factor regulating the antioxidant response. Nrf2 signaling is repressed by Keap1 at basal condition and induced by oxidative stress. Keap1 is recently identified as a Cullin 3-dependent substrate adaptor protein. A two-sites binding "hinge & latch" model vividly depicts how Keap1 can efficiently present Nrf2 as substrate for ubiquitination. Oxidative perturbation can impede Keap1-mediated Nrf2 ubiquitination but fail to disrupt Nrf2/Keap1 binding. Nrf2 per se is a redox-sensitive transcription factor. A new Nrf2-mediated redox signaling model is proposed based on these new discoveries. Free floating Nrf2 protein functions as a redox-sensitive probe. Keap1 instead functions as a gate keeper to control the availability of Nrf2 probes and thus regulates the overall sensitivity of the redox signaling. Copyright 2008 Wiley-Liss, Inc.
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            The chemical diversity and distribution of glucosinolates and isothiocyanates among plants.

            Glucosinolates (beta-thioglucoside-N-hydroxysulfates), the precursors of isothiocyanates, are present in sixteen families of dicotyledonous angiosperms including a large number of edible species. At least 120 different glucosinolates have been identified in these plants, although closely related taxonomic groups typically contain only a small number of such compounds. Glucosinolates and/or their breakdown products have long been known for their fungicidal, bacteriocidal, nematocidal and allelopathic properties and have recently attracted intense research interest because of their cancer chemoprotective attributes. Numerous reviews have addressed the occurrence of glucosinolates in vegetables, primarily the family Brassicaceae (syn. Cruciferae; including Brassica spp and Raphanus spp). The major focus of much previous research has been on the negative aspects of these compounds because of the prevalence of certain "antinutritional" or goitrogenic glucosinolates in the protein-rich defatted meal from widely grown oilseed crops and in some domesticated vegetable crops. There is, however, an opposite and positive side of this picture represented by the therapeutic and prophylactic properties of other "nutritional" or "functional" glucosinolates. This review addresses the complex array of these biologically active and chemically diverse compounds many of which have been identified during the past three decades in other families. In addition to the Brassica vegetables, these glucosinolates have been found in hundreds of species, many of which are edible or could provide substantial quantities of glucosinolates for isolation, for biological evaluation, and potential application as chemoprotective or other dietary or pharmacological agents.
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              Nrf2: friend or foe for chemoprevention?

              Health reflects the ability of an organism to adapt to stress. Stresses--metabolic, proteotoxic, mitotic, oxidative and DNA-damage stresses--not only contribute to the etiology of cancer and other chronic degenerative diseases but are also hallmarks of the cancer phenotype. Activation of the Kelch-like ECH-associated protein 1 (KEAP1)-NF-E2-related factor 2 (NRF2)-signaling pathway is an adaptive response to environmental and endogenous stresses and serves to render animals resistant to chemical carcinogenesis and other forms of toxicity, whilst disruption of the pathway exacerbates these outcomes. This pathway can be induced by thiol-reactive small molecules that demonstrate protective efficacy in preclinical chemoprevention models and in clinical trials. However, mutations and epigenetic modifications affecting the regulation and fate of NRF2 can lead to constitutive dominant hyperactivation of signaling that preserves rather than attenuates cancer phenotypes by providing selective resistance to stresses. This review provides a synopsis of KEAP1-NRF2 signaling, compares the impact of genetic versus pharmacologic activation and considers both the attributes and concerns of targeting the pathway in chemoprevention.
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                Author and article information

                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OXIMED
                Oxidative Medicine and Cellular Longevity
                Hindawi Publishing Corporation
                1942-0900
                1942-0994
                2013
                28 May 2013
                : 2013
                : 839409
                Affiliations
                College of Pharmacy, Dongguk University, 813-4 Siksa-dong, Goyang, Gyeonggi-do 410-820, Republic of Korea
                Author notes

                Academic Editor: Hye-Youn Cho

                Author information
                https://orcid.org/0000-0002-9348-466X
                Article
                10.1155/2013/839409
                3679808
                23781297
                707a8e67-fcf0-40e0-a051-4f3f1d199510
                Copyright © 2013 Biswa Nath Das et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 January 2013
                : 6 May 2013
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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