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      Nrf2 as a target for prevention of age‐related and diabetic cataracts by against oxidative stress

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          Summary

          Cataract is one of the most important causes of blindness worldwide, with age‐related cataract being the most common one. Agents preventing cataract formation are urgently required. Substantial evidences point out aggravated oxidative stress as a vital factor for cataract formation. Nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2)/Kelch‐like erythroid‐cell‐derived protein with CNC homology ( ECH)‐associated protein 1 (Keap1) system is considered as one of the main cellular defense mechanisms against oxidative stresses. This review discusses the role of Nrf2 pathway in the prevention of cataracts and highlights that Nrf2 suppressors may augment oxidative stress of the lens, and Nrf2 inducers may decrease the oxidative stress and prevent the cataract formation. Thus, Nrf2 may serve as a promising therapeutic target for cataract treatment.

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          Most cited references57

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          Genetics: influence of TOR kinase on lifespan in C. elegans.

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            PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress.

            The accumulation of unfolded proteins elicits a cellular response that triggers both pro-survival and pro-apoptotic signaling events. PERK-dependent activation of NF-E2-related factor-2 (Nrf2) is critical for survival signaling during this response; however, the mechanism whereby Nrf2 confers a protective advantage to stressed cells remains to be defined. We now demonstrate that Nrf2 activation contributes to the maintenance of glutathione levels, which in turn functions as a buffer for the accumulation of reactive oxygen species during the unfolded protein response. The deleterious effects of Nrf2 or PERK deficiencies could be attenuated by the restoration of cellular glutathione levels or Nrf2 activity. In addition, the inhibition of reactive oxygen species production attenuated apoptotic induction following endoplasmic reticulum stress. Our data suggest that perturbations in cellular redox status sensitize cells to the harmful effects of endoplasmic reticulum stress, but that other factors are essential for apoptotic commitment.
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              Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid.

              Glutathione (GSH) significantly declines in the aging rat liver. Because GSH levels are partly a reflection of its synthetic capacity, we measured the levels and activity of gamma-glutamylcysteine ligase (GCL), the rate-controlling enzyme in GSH synthesis. With age, both the catalytic (GCLC) and modulatory (GCLM) subunits of GCL decreased by 47% and 52%, respectively (P < 0.005). Concomitant with lower subunit levels, GCL activity also declined by 53% (P < 0.05). Because nuclear factor erythroid2-related factor 2 (Nrf2) governs basal and inducible GCLC and GCLM expression by means of the antioxidant response element (ARE), we hypothesized that aging results in dysregulation of Nrf2-mediated GCL expression. We observed an approximately 50% age-related loss in total (P < 0.001) and nuclear (P < 0.0001) Nrf2 levels, which suggests attenuation in Nrf2-dependent gene transcription. By using gel-shift and supershift assays, a marked reduction in Nrf2/ARE binding in old vs. young rats was noted. To determine whether the constitutive loss of Nrf2 transcriptional activity also affects the inducible nature of Nrf2 nuclear translocation, old rats were treated with (R)-alpha-lipoic acid (LA; 40 mg/kg i.p. up to 48 h), a disulfide compound shown to induce Nrf2 activation in vitro and improve GSH levels in vivo. LA administration increased nuclear Nrf2 levels in old rats after 12 h. LA also induced Nrf2 binding to the ARE, and, consequently, higher GCLC levels and GCL activity were observed 24 h after LA injection. Thus, the age-related loss in GSH synthesis may be caused by dysregulation of ARE-mediated gene expression, but chemoprotective agents, like LA, can attenuate this loss.
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                Author and article information

                Contributors
                lcwchina800@sina.com
                zhoudan0928@sohu.com
                Journal
                Aging Cell
                Aging Cell
                10.1111/(ISSN)1474-9726
                ACEL
                Aging Cell
                John Wiley and Sons Inc. (Hoboken )
                1474-9718
                1474-9726
                19 July 2017
                October 2017
                : 16
                : 5 ( doiID: 10.1111/acel.2017.16.issue-5 )
                : 934-942
                Affiliations
                [ 1 ] Department of Ophthalmology The First Hospital of Jilin University Jilin China
                [ 2 ] Department of Neurosurgery The People's Hospital of Jilin Province Jilin China
                [ 3 ] Department of Gastroenterology The First Hospital of Jilin University Jilin China
                [ 4 ] Department of Cardiology The First Hospital of Jiamusi University Heilongjiang China
                [ 5 ] Department of Obstetrics and Gynecology The First Hospital of Jilin University Jilin China
                [ 6 ] Department of Radiology The First Hospital of Jilin University Jilin China
                Author notes
                [*] [* ] Correspondence

                Cheng‐Wei Lu, Department of Ophthalmology, The First Hospital of Jilin University, Jilin, China. Tel.: +8615804301709; fax: +86043188782351; e‐mail : lcwchina800@ 123456sina.com

                and

                Dan‐Dan Zhou, Department of Radiology, The First Hospital of Jilin University, Jilin, China. Tel.: +8613756022530; fax: +86043188785577; e‐mail: zhoudan0928@ 123456sohu.com

                Article
                ACEL12645
                10.1111/acel.12645
                5595676
                28722304
                aab400b5-deed-421c-a7d3-86f38c92da89
                © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

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

                History
                : 12 June 2017
                Page count
                Figures: 2, Tables: 1, Pages: 9, Words: 7494
                Funding
                Funded by: Development and Reform Commission of Jilin Province
                Award ID: 2015Y031‐1
                Funded by: The First Hospital of Jilin University
                Award ID: JDYY72016055
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                acel12645
                October 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.9 mode:remove_FC converted:12.09.2017

                Cell biology
                antioxidant response element,cataracts,keap1,lenses,nrf2,oxidative stress
                Cell biology
                antioxidant response element, cataracts, keap1, lenses, nrf2, oxidative stress

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