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      Nrf2 drives oxidative stress-induced autophagy in nucleus pulposus cells via a Keap1/Nrf2/p62 feedback loop to protect intervertebral disc from degeneration

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          Abstract

          Intervertebral disc (IVD) degeneration is known to aggravate with age and oxidative stress is implicated in the pathogenesis of many age-related diseases. Nuclear factor (erythroid-derived-2)-like 2 (Nrf2) can confer adaptive protection against oxidative and proteotoxic stress in cells. In this study, we assessed whether Nrf2 can protect against oxidative stress in nucleus pulposus (NP) cells. In addition, we investigated Nrf2 expression in NP tissue samples from patients with different degrees of IVD degeneration and a mouse model of aging and IVD degeneration and the influence of H 2O 2-induced oxidative stress on autophagic pathways in NP cells. Autophagy was assessed by measuring levels of autophagy-related protein (ATG) family members and the autophagic markers, p62 and LC3. We found that expression of Nrf2 progressively decreased in human NP tissue samples of patients with increasing degrees of IVD degeneration. Nrf2 deficiency leads to the degeneration of IVDs during aging. Nrf2 knockout also aggravates IVD degeneration and reduces autophagic gene expression in an induced mouse model of IVD degeneration. The detrimental effects of H 2O 2-induced oxidative stress were increased in autophagy-deficient cells via reduced expression of Atg7 and the Keap1–Nrf2–p62 autophagy pathway. Taken together, these results suggest that excessive oxidative stress causes the upregulation of autophagy, and autophagy acts as an antioxidant feedback response activated by a Keap1-Nrf2-p62 feedback loop in IVD degeneration.

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          Most cited references 35

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          Magnetic resonance classification of lumbar intervertebral disc degeneration.

          A reliability study was conducted. To develop a classification system for lumbar disc degeneration based on routine magnetic resonance imaging, to investigate the applicability of a simple algorithm, and to assess the reliability of this classification system. A standardized nomenclature in the assessment of disc abnormalities is a prerequisite for a comparison of data from different investigations. The reliability of the assessment has a crucial influence on the validity of the data. Grading systems of disc degeneration based on state of the art magnetic resonance imaging and corresponding reproducibility studies currently are sparse. A grading system for lumbar disc degeneration was developed on the basis of the literature. An algorithm to assess the grading was developed and optimized by reviewing lumbar magnetic resonance examinations. The reliability of the algorithm in depicting intervertebral disc alterations was tested on the magnetic resonance images of 300 lumbar intervertebral discs in 60 patients (33 men and 27 women) with a mean age of 40 years (range, 10-83 years). All scans were analyzed independently by three observers. Intra- and interobserver reliabilities were assessed by calculating kappa statistics. There were 14 Grade I, 82 Grade II, 72 Grade III, 68 Grade IV, and 64 Grade V discs. The kappa coefficients for intra- and interobserver agreement were substantial to excellent: intraobserver (kappa range, 0.84-0.90) and interobserver (kappa range, 0.69-0.81). Complete agreement was obtained, on the average, in 83.8% of all the discs. A difference of one grade occurred in 15.9% and a difference of two or more grades in 1.3% of all the cases. Disc degeneration can be graded reliably on routine T2-weighted magnetic resonance images using the grading system and algorithm presented in this investigation.
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            Role of nrf2 in oxidative stress and toxicity.

             Jian-Qiang Ma (2012)
            Organismal life encounters reactive oxidants from internal metabolism and environmental toxicant exposure. Reactive oxygen and nitrogen species cause oxidative stress and are traditionally viewed as being harmful. On the other hand, controlled production of oxidants in normal cells serves useful purposes to regulate signaling pathways. Reactive oxidants are counterbalanced by complex antioxidant defense systems regulated by a web of pathways to ensure that the response to oxidants is adequate for the body's needs. A recurrent theme in oxidant signaling and antioxidant defense is reactive cysteine thiol-based redox signaling. The nuclear factor erythroid 2-related factor 2 (Nrf2) is an emerging regulator of cellular resistance to oxidants. Nrf2 controls the basal and induced expression of an array of antioxidant response element-dependent genes to regulate the physiological and pathophysiological outcomes of oxidant exposure. This review discusses the impact of Nrf2 on oxidative stress and toxicity and how Nrf2 senses oxidants and regulates antioxidant defense.
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              Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution.

              The Keap1–Nrf2 regulatory pathway plays a central role in the protection of cells against oxidative and xenobiotic damage. Under unstressed conditions, Nrf2 is constantly ubiquitinated by the Cul3–Keap1 ubiquitin E3 ligase complex and rapidly degraded in proteasomes. Upon exposure to electrophilic and oxidative stresses, reactive cysteine residues of Keap1 become modified, leading to a decline in the E3 ligase activity, stabilization of Nrf2 and robust induction of a battery of cytoprotective genes. Biochemical and structural analyses have revealed that the intact Keap1 homodimer forms a cherry-bob structure in which one molecule of Nrf2 associates with two molecules of Keap1 by using two binding sites within the Neh2 domain of Nrf2. This two-site binding appears critical for Nrf2 ubiquitination. In many human cancers, missense mutations in KEAP1 and NRF2 genes have been identified. These mutations disrupt the Keap1–Nrf2 complex activity involved in ubiquitination and degradation of Nrf2 and result in constitutive activation of Nrf2. Elevated expression of Nrf2 target genes confers advantages in terms of stress resistance and cell proliferation in normal and cancer cells. Discovery and development of selective Nrf2 inhibitors should make a critical contribution to improved cancer therapy.
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                Author and article information

                Contributors
                +(86) 021-81885621 , spine.chen@163.com
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                1 July 2019
                1 July 2019
                July 2019
                : 10
                : 7
                Affiliations
                ISNI 0000 0004 0369 1660, GRID grid.73113.37, Department of Spinal Surgery, Changzheng Hospital, , Second Military Medical University, ; Shanghai, China
                Article
                1701
                10.1038/s41419-019-1701-3
                6602960
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                © The Author(s) 2019

                Cell biology

                autophagy, cell signalling

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