Cargando…

2-Methoxy-7-Acetonyljuglone Isolated from Reynoutria japonica Increases the Activity of Nuclear Factor Erythroid 2-Related Factor-2 through Inhibition of Ubiquitin Degradation in HeLa Cells

The nuclear factor erythroid-derived 2-related factor 2 (NRF2) is a key transcription factor for the activation of genes responsible for oxidative stress and drug detoxification. Thus, it is important to identify NRF2 activators, which can be used to protect the cells from oxidative damage. Here, we...

Descripción completa

Detalles Bibliográficos
Autores principales: Kim, Jung-Hwan, Khalil, Atif Ali Khan, Kim, Hye-Jin, Kim, Sung-Eun, Ahn, Mi-Jeong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770542/
https://www.ncbi.nlm.nih.gov/pubmed/31540074
http://dx.doi.org/10.3390/antiox8090398
_version_ 1783455497737732096
author Kim, Jung-Hwan
Khalil, Atif Ali Khan
Kim, Hye-Jin
Kim, Sung-Eun
Ahn, Mi-Jeong
author_facet Kim, Jung-Hwan
Khalil, Atif Ali Khan
Kim, Hye-Jin
Kim, Sung-Eun
Ahn, Mi-Jeong
author_sort Kim, Jung-Hwan
collection PubMed
description The nuclear factor erythroid-derived 2-related factor 2 (NRF2) is a key transcription factor for the activation of genes responsible for oxidative stress and drug detoxification. Thus, it is important to identify NRF2 activators, which can be used to protect the cells from oxidative damage. Here, we investigated the effect of juglone derivatives isolated from Reynoutria japonica on the activity of NRF2 in HeLa cells. We demonstrated that among the juglone derivatives, 2-methoxy-7-acetonyljuglone (MA) strongly stimulated the antioxidant response element (ARE)-luciferase activity in a dose-dependent manner. In addition, MA significantly increased the nuclear localization of NRF2 and, consequently, increased the expression of NRF2 target genes, including heme oxygenase-1(HO-1), NAD(P)H: quinine oxidoreductase-1 (NQO-1), and glutamate-cysteine ligase catalytic (GCLC). To gain insights into the NRF2 signaling mechanism by MA, we measured the activities of RAC-alpha serine/threonine-protein kinase (AKT) and mitogen-activated protein (MAP) kinase family proteins, including extracellular signal-regulated kinase (ERK) and p38. Our results showed that MA induced NRF2 activity through p38 and AKT signaling. Subsequently, we found that MA significantly enhanced NRF2 stability by inhibiting ubiquitin-dependent proteasomal degradation. Thus, MA might protect cells by enhancing the activity and stability of NRF2 through inhibition of the proteasomal degradation pathway.
format Online
Article
Text
id pubmed-6770542
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-67705422019-10-30 2-Methoxy-7-Acetonyljuglone Isolated from Reynoutria japonica Increases the Activity of Nuclear Factor Erythroid 2-Related Factor-2 through Inhibition of Ubiquitin Degradation in HeLa Cells Kim, Jung-Hwan Khalil, Atif Ali Khan Kim, Hye-Jin Kim, Sung-Eun Ahn, Mi-Jeong Antioxidants (Basel) Article The nuclear factor erythroid-derived 2-related factor 2 (NRF2) is a key transcription factor for the activation of genes responsible for oxidative stress and drug detoxification. Thus, it is important to identify NRF2 activators, which can be used to protect the cells from oxidative damage. Here, we investigated the effect of juglone derivatives isolated from Reynoutria japonica on the activity of NRF2 in HeLa cells. We demonstrated that among the juglone derivatives, 2-methoxy-7-acetonyljuglone (MA) strongly stimulated the antioxidant response element (ARE)-luciferase activity in a dose-dependent manner. In addition, MA significantly increased the nuclear localization of NRF2 and, consequently, increased the expression of NRF2 target genes, including heme oxygenase-1(HO-1), NAD(P)H: quinine oxidoreductase-1 (NQO-1), and glutamate-cysteine ligase catalytic (GCLC). To gain insights into the NRF2 signaling mechanism by MA, we measured the activities of RAC-alpha serine/threonine-protein kinase (AKT) and mitogen-activated protein (MAP) kinase family proteins, including extracellular signal-regulated kinase (ERK) and p38. Our results showed that MA induced NRF2 activity through p38 and AKT signaling. Subsequently, we found that MA significantly enhanced NRF2 stability by inhibiting ubiquitin-dependent proteasomal degradation. Thus, MA might protect cells by enhancing the activity and stability of NRF2 through inhibition of the proteasomal degradation pathway. MDPI 2019-09-14 /pmc/articles/PMC6770542/ /pubmed/31540074 http://dx.doi.org/10.3390/antiox8090398 Text en © 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/).
spellingShingle Article
Kim, Jung-Hwan
Khalil, Atif Ali Khan
Kim, Hye-Jin
Kim, Sung-Eun
Ahn, Mi-Jeong
2-Methoxy-7-Acetonyljuglone Isolated from Reynoutria japonica Increases the Activity of Nuclear Factor Erythroid 2-Related Factor-2 through Inhibition of Ubiquitin Degradation in HeLa Cells
title 2-Methoxy-7-Acetonyljuglone Isolated from Reynoutria japonica Increases the Activity of Nuclear Factor Erythroid 2-Related Factor-2 through Inhibition of Ubiquitin Degradation in HeLa Cells
title_full 2-Methoxy-7-Acetonyljuglone Isolated from Reynoutria japonica Increases the Activity of Nuclear Factor Erythroid 2-Related Factor-2 through Inhibition of Ubiquitin Degradation in HeLa Cells
title_fullStr 2-Methoxy-7-Acetonyljuglone Isolated from Reynoutria japonica Increases the Activity of Nuclear Factor Erythroid 2-Related Factor-2 through Inhibition of Ubiquitin Degradation in HeLa Cells
title_full_unstemmed 2-Methoxy-7-Acetonyljuglone Isolated from Reynoutria japonica Increases the Activity of Nuclear Factor Erythroid 2-Related Factor-2 through Inhibition of Ubiquitin Degradation in HeLa Cells
title_short 2-Methoxy-7-Acetonyljuglone Isolated from Reynoutria japonica Increases the Activity of Nuclear Factor Erythroid 2-Related Factor-2 through Inhibition of Ubiquitin Degradation in HeLa Cells
title_sort 2-methoxy-7-acetonyljuglone isolated from reynoutria japonica increases the activity of nuclear factor erythroid 2-related factor-2 through inhibition of ubiquitin degradation in hela cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770542/
https://www.ncbi.nlm.nih.gov/pubmed/31540074
http://dx.doi.org/10.3390/antiox8090398
work_keys_str_mv AT kimjunghwan 2methoxy7acetonyljugloneisolatedfromreynoutriajaponicaincreasestheactivityofnuclearfactorerythroid2relatedfactor2throughinhibitionofubiquitindegradationinhelacells
AT khalilatifalikhan 2methoxy7acetonyljugloneisolatedfromreynoutriajaponicaincreasestheactivityofnuclearfactorerythroid2relatedfactor2throughinhibitionofubiquitindegradationinhelacells
AT kimhyejin 2methoxy7acetonyljugloneisolatedfromreynoutriajaponicaincreasestheactivityofnuclearfactorerythroid2relatedfactor2throughinhibitionofubiquitindegradationinhelacells
AT kimsungeun 2methoxy7acetonyljugloneisolatedfromreynoutriajaponicaincreasestheactivityofnuclearfactorerythroid2relatedfactor2throughinhibitionofubiquitindegradationinhelacells
AT ahnmijeong 2methoxy7acetonyljugloneisolatedfromreynoutriajaponicaincreasestheactivityofnuclearfactorerythroid2relatedfactor2throughinhibitionofubiquitindegradationinhelacells