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      Curcumin Protects Human Trophoblast HTR8/SVneo Cells from H 2O 2-Induced Oxidative Stress by Activating Nrf2 Signaling Pathway

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      Author(s): , , , , *
      Publication date (Electronic):
      Journal: Antioxidants
      Publisher: MDPI
      Keywords: curcumin, HTR8/SVneo cells, Nrf2, oxidative stress

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          Abstract

          Pregnancy complications are associated with oxidative stress induced by accumulation of trophoblastic ROS in the placenta. We employed the human trophoblast HTR8/SVneo cell line to determine the effect of curcumin pre-treatment on H 2O 2-induced oxidative damage in HTR8/Sveo cells. Cells were pretreated with 2.5 or 5 μM curcumin for 24 h, and then incubated with 400 μM H 2O 2 for another 24 h. The results showed that H 2O 2 decreased the cell viability and induced excessive accumulation of reactive oxygen species (ROS) in HTR8/Sveo cells. Curcumin pre-treatment effectively protected HTR8/SVneo cells against oxidative stress-induced apoptosis via increasing Bcl-2/Bax ratio and decreasing the protein expression level of cleaved-caspase 3. Moreover, curcumin pre-treatment alleviated the excessive oxidative stress by enhancing the activity of antioxidative enzymes. The antioxidant effect of curcumin was achieved by activating Nrf2 and its downstream antioxidant proteins. In addition, knockdown of Nrf2 by Nrf2-siRNA transfection abolished the protective effects of curcumin on HTR8/SVneo cells against oxidative damage. Taken together, our results show that curcumin could protect HTR8/SVneo cells from H 2O 2-induced oxidative stress by activating Nrf2 signaling pathway.

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          Glutathione peroxidases.

          Regina Brigelius-Flohé, Matilde Maiorino (2013)
          With increasing evidence that hydroperoxides are not only toxic but rather exert essential physiological functions, also hydroperoxide removing enzymes have to be re-viewed. In mammals, the peroxidases inter alia comprise the 8 glutathione peroxidases (GPx1-GPx8) so far identified. Since GPxs have recently been reviewed under various aspects, we here focus on novel findings considering their diverse physiological roles exceeding an antioxidant activity. GPxs are involved in balancing the H2O2 homeostasis in signalling cascades, e.g. in the insulin signalling pathway by GPx1; GPx2 plays a dual role in carcinogenesis depending on the mode of initiation and cancer stage; GPx3 is membrane associated possibly explaining a peroxidatic function despite low plasma concentrations of GSH; GPx4 has novel roles in the regulation of apoptosis and, together with GPx5, in male fertility. Functions of GPx6 are still unknown, and the proposed involvement of GPx7 and GPx8 in protein folding awaits elucidation. Collectively, selenium-containing GPxs (GPx1-4 and 6) as well as their non-selenium congeners (GPx5, 7 and 8) became key players in important biological contexts far beyond the detoxification of hydroperoxides. This article is part of a Special Issue entitled Cellular functions of glutathione. Copyright © 2012 Elsevier B.V. All rights reserved.
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            Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution.

            Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto (2011)
            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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              Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element.

              Elisabeth Balogun, Martha Hoque, Pengfei Gong … (2003)
              The transcription factor Nrf2, which normally exists in an inactive state as a consequence of binding to a cytoskeleton-associated protein Keap1, can be activated by redox-dependent stimuli. Alteration of the Nrf2-Keap1 interaction enables Nrf2 to translocate to the nucleus, bind to the antioxidant-responsive element (ARE) and initiate the transcription of genes coding for detoxifying enzymes and cytoprotective proteins. This response is also triggered by a class of electrophilic compounds including polyphenols and plant-derived constituents. Recently, the natural antioxidants curcumin and caffeic acid phenethyl ester (CAPE) have been identified as potent inducers of haem oxygenase-1 (HO-1), a redox-sensitive inducible protein that provides protection against various forms of stress. Here, we show that in renal epithelial cells both curcumin and CAPE stimulate the expression of Nrf2 in a concentration- and time-dependent manner. This effect was associated with a significant increase in HO-1 protein expression and haem oxygenase activity. From several lines of investigation we also report that curcumin (and, by inference, CAPE) stimulates ho-1 gene activity by promoting inactivation of the Nrf2-Keap1 complex, leading to increased Nrf2 binding to the resident ho-1 AREs. Moreover, using antibodies and specific inhibitors of the mitogen-activated protein kinase (MAPK) pathways, we provide data implicating p38 MAPK in curcumin-mediated ho-1 induction. Taken together, these results demonstrate that induction of HO-1 by curcumin and CAPE requires the activation of the Nrf2/ARE pathway.
              Article 0 comments Cited 256 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Antioxidants (Basel)
                Journal ID (iso-abbrev): Antioxidants (Basel)
                Journal ID (publisher-id): antioxidants
                Title: Antioxidants
                Publisher: MDPI
                ISSN (Electronic): 2076-3921
                Publication date (Electronic): 01 February 2020
                Publication date Collection: February 2020
                Volume: 9
                Issue: 2
                Electronic Location Identifier: 121
                Affiliations
                National Experimental Teaching Demonstration Center of Animal Science, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; 2018205023@ 123456njau.edu.cn (L.Q.); 2018205008@ 123456njau.edu.cn (J.J.); zhangjingfei@ 123456njau.edu.cn (J.Z.); zhanglili@ 123456njau.edu.cn (L.Z.)
                Author notes
                [* ]Correspondence: tianwangnjau@ 123456163.com
                Article
                Publisher ID: antioxidants-09-00121
                DOI: 10.3390/antiox9020121
                PMC ID: 7071057
                PubMed ID: 32024207
                SO-VID: e9f0e17f-91d3-4655-b0fd-c06f8a3e05e2
                Copyright © © 2020 by the authors.
                License:

                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
                Date received : 15 January 2020
                Date accepted : 29 January 2020
                Categories
                Subject: Article

                Keywords: curcumin,htr8/svneo cells,nrf2,oxidative stress
                Data availability:
                Keywords: curcumin, htr8/svneo cells, nrf2, oxidative stress

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