Novel Nrf2/ARE Activator, trans-Coniferylaldehyde, Induces a HO-1-Mediated Defense Mechanism through a Dual p38α/MAPKAPK-2 and PK-N3 Signaling Pathway

Huang Hui Chen, Tai Chi Wang, Yen Chen Lee, Pei Ting Shen, Jang Yang Chang, Teng Kuang Yeh, Chih Hsiang Huang, Hsin Huei Chang, Shu Ying Cheng, Chin Yu Lin, Chuan Shih, Chiung Tong Chen, Wei Min Liu, Ching Hui Chen, Ching Chuan Kuo

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The induction of detoxifying enzymes and antioxidant proteins by chemopreventive agents protects cells from oxidizing substances capable of damaging DNA integrity and initiating carcinogenesis. Coniferyl aldehyde, a naturally occurring substance, has been found in many foods and edible plants. We and others previously demonstrated that trans-coniferylaldehyde (t-CA) has potential antimutagenic and antioxidant properties. However, the mechanism underlying its Nrf2-mediated antioxidant effect remains largely unknown. In the present study, we demonstrated that t-CA significantly stimulated antioxidant-responsive element (ARE)-driven luciferase activity in a cell model and increased the expression of ARE-dependent detoxifying/antioxidant genes and their protein products in vitro and in vivo. The detoxifying/antioxidant genes activated by t-CA, especially heme oxygenase-1 (HO-1), were found to be involved in its cytoprotective effects against oxidative stress and cell injuries elicited by carcinogens tert-butylhydroperoxide and arecoline. Furthermore, the t-CA-induced phosphorylation and nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) played a crucial role in this ARE-mediated cellular defense. Moreover, we found that p38 MAPK and protein kinase C (PKC) signaling pathways participated in the t-CA-induced, Nrf2-mediated cytoprotective effect. Among them, p38α/MAPKAPK-2 and an atypical PKC, PK-N3, were critical for the activation of the Nrf2/HO-1 axis by t-CA. In conclusion, we demonstrated for the first time that t-CA attenuates carcinogen-induced oxidative stress by activating Nrf2 via p38α/MAPKAPK-2- and PK-N3-dependent signaling pathways. In addition, t-CA increased the level of Nrf2-mediated detoxifying/antioxidant proteins in vivo, suggesting that t-CA may have potential for use in the management of carcinogenesis and meriting further investigation.

Original languageEnglish
Pages (from-to)1681-1692
Number of pages12
JournalChemical Research in Toxicology
Volume28
Issue number9
DOIs
Publication statusPublished - Aug 14 2015

Fingerprint

Heme Oxygenase-1
Antioxidants
Edible Plants
Oxidative stress
p38 Mitogen-Activated Protein Kinases
Carcinogens
Carcinogenesis
Oxidative Stress
Arecoline
coniferaldehyde
MAP-kinase-activated kinase 2
tert-Butylhydroperoxide
Phosphorylation
Enzyme Induction
Proteins
Mitogen-Activated Protein Kinase Kinases
Luciferases
Protein Kinase C
Genes
Chemical activation

ASJC Scopus subject areas

  • Toxicology

Cite this

Novel Nrf2/ARE Activator, trans-Coniferylaldehyde, Induces a HO-1-Mediated Defense Mechanism through a Dual p38α/MAPKAPK-2 and PK-N3 Signaling Pathway. / Chen, Huang Hui; Wang, Tai Chi; Lee, Yen Chen; Shen, Pei Ting; Chang, Jang Yang; Yeh, Teng Kuang; Huang, Chih Hsiang; Chang, Hsin Huei; Cheng, Shu Ying; Lin, Chin Yu; Shih, Chuan; Chen, Chiung Tong; Liu, Wei Min; Chen, Ching Hui; Kuo, Ching Chuan.

In: Chemical Research in Toxicology, Vol. 28, No. 9, 14.08.2015, p. 1681-1692.

Research output: Contribution to journalArticle

Chen, HH, Wang, TC, Lee, YC, Shen, PT, Chang, JY, Yeh, TK, Huang, CH, Chang, HH, Cheng, SY, Lin, CY, Shih, C, Chen, CT, Liu, WM, Chen, CH & Kuo, CC 2015, 'Novel Nrf2/ARE Activator, trans-Coniferylaldehyde, Induces a HO-1-Mediated Defense Mechanism through a Dual p38α/MAPKAPK-2 and PK-N3 Signaling Pathway', Chemical Research in Toxicology, vol. 28, no. 9, pp. 1681-1692. https://doi.org/10.1021/acs.chemrestox.5b00085
Chen, Huang Hui ; Wang, Tai Chi ; Lee, Yen Chen ; Shen, Pei Ting ; Chang, Jang Yang ; Yeh, Teng Kuang ; Huang, Chih Hsiang ; Chang, Hsin Huei ; Cheng, Shu Ying ; Lin, Chin Yu ; Shih, Chuan ; Chen, Chiung Tong ; Liu, Wei Min ; Chen, Ching Hui ; Kuo, Ching Chuan. / Novel Nrf2/ARE Activator, trans-Coniferylaldehyde, Induces a HO-1-Mediated Defense Mechanism through a Dual p38α/MAPKAPK-2 and PK-N3 Signaling Pathway. In: Chemical Research in Toxicology. 2015 ; Vol. 28, No. 9. pp. 1681-1692.
@article{e0e6e33717394b16bf30e86b481a82f6,
title = "Novel Nrf2/ARE Activator, trans-Coniferylaldehyde, Induces a HO-1-Mediated Defense Mechanism through a Dual p38α/MAPKAPK-2 and PK-N3 Signaling Pathway",
abstract = "The induction of detoxifying enzymes and antioxidant proteins by chemopreventive agents protects cells from oxidizing substances capable of damaging DNA integrity and initiating carcinogenesis. Coniferyl aldehyde, a naturally occurring substance, has been found in many foods and edible plants. We and others previously demonstrated that trans-coniferylaldehyde (t-CA) has potential antimutagenic and antioxidant properties. However, the mechanism underlying its Nrf2-mediated antioxidant effect remains largely unknown. In the present study, we demonstrated that t-CA significantly stimulated antioxidant-responsive element (ARE)-driven luciferase activity in a cell model and increased the expression of ARE-dependent detoxifying/antioxidant genes and their protein products in vitro and in vivo. The detoxifying/antioxidant genes activated by t-CA, especially heme oxygenase-1 (HO-1), were found to be involved in its cytoprotective effects against oxidative stress and cell injuries elicited by carcinogens tert-butylhydroperoxide and arecoline. Furthermore, the t-CA-induced phosphorylation and nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) played a crucial role in this ARE-mediated cellular defense. Moreover, we found that p38 MAPK and protein kinase C (PKC) signaling pathways participated in the t-CA-induced, Nrf2-mediated cytoprotective effect. Among them, p38α/MAPKAPK-2 and an atypical PKC, PK-N3, were critical for the activation of the Nrf2/HO-1 axis by t-CA. In conclusion, we demonstrated for the first time that t-CA attenuates carcinogen-induced oxidative stress by activating Nrf2 via p38α/MAPKAPK-2- and PK-N3-dependent signaling pathways. In addition, t-CA increased the level of Nrf2-mediated detoxifying/antioxidant proteins in vivo, suggesting that t-CA may have potential for use in the management of carcinogenesis and meriting further investigation.",
author = "Chen, {Huang Hui} and Wang, {Tai Chi} and Lee, {Yen Chen} and Shen, {Pei Ting} and Chang, {Jang Yang} and Yeh, {Teng Kuang} and Huang, {Chih Hsiang} and Chang, {Hsin Huei} and Cheng, {Shu Ying} and Lin, {Chin Yu} and Chuan Shih and Chen, {Chiung Tong} and Liu, {Wei Min} and Chen, {Ching Hui} and Kuo, {Ching Chuan}",
year = "2015",
month = "8",
day = "14",
doi = "10.1021/acs.chemrestox.5b00085",
language = "English",
volume = "28",
pages = "1681--1692",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
publisher = "American Chemical Society",
number = "9",

}

TY - JOUR

T1 - Novel Nrf2/ARE Activator, trans-Coniferylaldehyde, Induces a HO-1-Mediated Defense Mechanism through a Dual p38α/MAPKAPK-2 and PK-N3 Signaling Pathway

AU - Chen, Huang Hui

AU - Wang, Tai Chi

AU - Lee, Yen Chen

AU - Shen, Pei Ting

AU - Chang, Jang Yang

AU - Yeh, Teng Kuang

AU - Huang, Chih Hsiang

AU - Chang, Hsin Huei

AU - Cheng, Shu Ying

AU - Lin, Chin Yu

AU - Shih, Chuan

AU - Chen, Chiung Tong

AU - Liu, Wei Min

AU - Chen, Ching Hui

AU - Kuo, Ching Chuan

PY - 2015/8/14

Y1 - 2015/8/14

N2 - The induction of detoxifying enzymes and antioxidant proteins by chemopreventive agents protects cells from oxidizing substances capable of damaging DNA integrity and initiating carcinogenesis. Coniferyl aldehyde, a naturally occurring substance, has been found in many foods and edible plants. We and others previously demonstrated that trans-coniferylaldehyde (t-CA) has potential antimutagenic and antioxidant properties. However, the mechanism underlying its Nrf2-mediated antioxidant effect remains largely unknown. In the present study, we demonstrated that t-CA significantly stimulated antioxidant-responsive element (ARE)-driven luciferase activity in a cell model and increased the expression of ARE-dependent detoxifying/antioxidant genes and their protein products in vitro and in vivo. The detoxifying/antioxidant genes activated by t-CA, especially heme oxygenase-1 (HO-1), were found to be involved in its cytoprotective effects against oxidative stress and cell injuries elicited by carcinogens tert-butylhydroperoxide and arecoline. Furthermore, the t-CA-induced phosphorylation and nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) played a crucial role in this ARE-mediated cellular defense. Moreover, we found that p38 MAPK and protein kinase C (PKC) signaling pathways participated in the t-CA-induced, Nrf2-mediated cytoprotective effect. Among them, p38α/MAPKAPK-2 and an atypical PKC, PK-N3, were critical for the activation of the Nrf2/HO-1 axis by t-CA. In conclusion, we demonstrated for the first time that t-CA attenuates carcinogen-induced oxidative stress by activating Nrf2 via p38α/MAPKAPK-2- and PK-N3-dependent signaling pathways. In addition, t-CA increased the level of Nrf2-mediated detoxifying/antioxidant proteins in vivo, suggesting that t-CA may have potential for use in the management of carcinogenesis and meriting further investigation.

AB - The induction of detoxifying enzymes and antioxidant proteins by chemopreventive agents protects cells from oxidizing substances capable of damaging DNA integrity and initiating carcinogenesis. Coniferyl aldehyde, a naturally occurring substance, has been found in many foods and edible plants. We and others previously demonstrated that trans-coniferylaldehyde (t-CA) has potential antimutagenic and antioxidant properties. However, the mechanism underlying its Nrf2-mediated antioxidant effect remains largely unknown. In the present study, we demonstrated that t-CA significantly stimulated antioxidant-responsive element (ARE)-driven luciferase activity in a cell model and increased the expression of ARE-dependent detoxifying/antioxidant genes and their protein products in vitro and in vivo. The detoxifying/antioxidant genes activated by t-CA, especially heme oxygenase-1 (HO-1), were found to be involved in its cytoprotective effects against oxidative stress and cell injuries elicited by carcinogens tert-butylhydroperoxide and arecoline. Furthermore, the t-CA-induced phosphorylation and nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) played a crucial role in this ARE-mediated cellular defense. Moreover, we found that p38 MAPK and protein kinase C (PKC) signaling pathways participated in the t-CA-induced, Nrf2-mediated cytoprotective effect. Among them, p38α/MAPKAPK-2 and an atypical PKC, PK-N3, were critical for the activation of the Nrf2/HO-1 axis by t-CA. In conclusion, we demonstrated for the first time that t-CA attenuates carcinogen-induced oxidative stress by activating Nrf2 via p38α/MAPKAPK-2- and PK-N3-dependent signaling pathways. In addition, t-CA increased the level of Nrf2-mediated detoxifying/antioxidant proteins in vivo, suggesting that t-CA may have potential for use in the management of carcinogenesis and meriting further investigation.

UR - http://www.scopus.com/inward/record.url?scp=84941884870&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941884870&partnerID=8YFLogxK

U2 - 10.1021/acs.chemrestox.5b00085

DO - 10.1021/acs.chemrestox.5b00085

M3 - Article

C2 - 26275128

AN - SCOPUS:84941884870

VL - 28

SP - 1681

EP - 1692

JO - Chemical Research in Toxicology

JF - Chemical Research in Toxicology

SN - 0893-228X

IS - 9

ER -