Mitochondrion-Mediated Apoptosis Induced by Acrylamide is Regulated by a Balance Between Nrf2 Antioxidant and MAPK Signaling Pat

Mitochondrion-Mediated Apoptosis Induced by Acrylamide is Regulated by a Balance Between Nrf2 Antioxidant and MAPK Signaling Pathways in PC12 Cells | Molecular Neurobiology | Springer Nature Link
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Mitochondrion-Mediated Apoptosis Induced by Acrylamide is Regulated by a Balance Between Nrf2 Antioxidant and MAPK Signaling Pathways in PC12 Cells
Published:
08 August 2016
Volume 54
, pages 4781–4794, (
2017
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Molecular Neurobiology
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Abstract
Acrylamide (ACR) is a potent toxin that affects the human nervous system. However, the underlying mechanism of ACR neurotoxicity remains poorly understood. In the present study, we investigated whether ACR induces mitochondrion-dependent apoptosis and the involved signaling pathways in PC12 cells. ACR exposure activated the mitochondrial apoptotic pathway in PC12 cells and triggered the up-regulation of Bax/Bcl-2 ratio, excessive release of cytochrome c, cleavage of capase-9 and caspase-3, depolarization of the mitochondrial membrane, structural damages to the mitochondria, and compaction of nuclear heterochromatin. ACR-induced oxidative stress was also observed based on distinct increase in cellular reactive oxygen species (ROS) and malondialdehyde (MDA), and significant decrease in glutathione (GSH). Mitogen-activated protein kinases (MAPK) signaling including extracellular signal-regulated protein kinases (ERK), c-Jun N-terminal kinases (JNK), and p38 were phosphorylated by ROS overproduction in PC12 cells in a time-and dose-dependent manner. ACR promoted the translocation of nuclear factor E2-related factor 2 (Nrf2) from the cytosol to the nucleus, thereby enhancing the expression of downstream γ-glutamyl-cysteine synthetase (γ-GCS). The regulation of Nrf2 activation by MAPK pathways was confirmed by the blockade of MAPK pathways. The suppression of JNK and p38 pathways showed a protective effect on ACR-induced mitochondrial dysfunction and apoptosis. Nrf2 knockdown further enhanced MDA production and reduced GSH generation induced by ACR. These results suggest that MAPK and Nrf2 signaling pathways contribute to mitochondrion-mediated apoptosis induced by ACR in PC12 cells.
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Mechanism of Action
Nitrosylation
Toxicology
Acrylamide Toxicology and Neuroprotective Mechanisms
Abbreviations
ACR:
Acrylamide
Nrf2:
Nuclear transcription factor E2-related factor 2
MAPK:
Mitogen activated protein kinase
ERK:
Extracellular signal regulated protein kinase
JNK:
c-Jun N-terminal kinase
ROS:
Reactive oxygen species
MDA:
Malondialdehvde
GSH:
Glutathione
γ-GCS:
γ-Glutamyl-cysteine synthetase
MMP:
Mitochondrial membrane potential
DMSO:
Dimethylsulfoxide
FBS:
Fetal bovine serum
PI:
Propidium iodide
MTT:
3–4, 5-Dimethylthiazol-2-yl-2, 5-diphenyltetrazoliumbromide
JC-1:
5–5, 6–6-Tetrachloro-1, 1, 3, 3-tetra-ethylbenzimidazolcarbocya-nine iodide
DAPI:
4′,6-Diamidino-2-phenylindole
DCFH-DA:
2, 7-Dichlorofluorescein diacetate
TBA:
Thiobarbituric acid;
BSA:
Bull serum albumin
PBS:
Phosphate buffer solution
TEM:
Transmission electron microscopy
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Acknowledgments
We appreciate the contribution of all the members participating in this study. The work was financially supported by the National Natural Science Foundation of China (No. 81373042).
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Authors and Affiliations
Department of Health Toxicology, MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong-Road, Wuhan, Hubei, 430030, People’s Republic of China
Xiaoqi Pan, Dandan Yan, Dun Wang, Xu Wu, Wanyun Zhao, Qing Lu & Hong Yan
School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, 611130, China
Xiaoqi Pan
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Pan, X., Yan, D., Wang, D.
et al.
Mitochondrion-Mediated Apoptosis Induced by Acrylamide is Regulated by a Balance Between Nrf2 Antioxidant and MAPK Signaling Pathways in PC12 Cells.
Mol Neurobiol
54
, 4781–4794 (2017). https://doi.org/10.1007/s12035-016-0021-1
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Received
19 February 2016
Accepted
01 August 2016
Published
08 August 2016
Issue date
August 2017
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Keywords
Acrylamide
Oxidative stress
Apoptosis
Nrf2
MAPK
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