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Bilirubin mediated oxidative stress involves antioxidant response activation via Nrf2 pathway.
Cell Signal. 2014 Mar; 26(3):512-20.CS

Abstract

Unconjugated bilirubin (UCB) is responsible for neonatal jaundice and high level of free bilirubin (Bf) can lead to kernicterus. Previous studies suggest that oxidative stress is a critical component of UCB-induced neurotoxicity. The Nrf2 pathway is a powerful sensor for cellular redox state and is activated directly by oxidative stress and/or indirectly by stress response protein kinases. Activated Nrf2 translocates to nucleus, binds to Antioxidant Response Element (ARE), and enhances the up-regulation of cytoprotective genes that mediate cell survival. The aim of the present study was to investigate the role of Nrf2 pathway in cell response to bilirubin mediated oxidative stress in the neuroblastoma SH-SY5Y cell line. Cells exposed to a toxic concentration of UCB (140 nM Bf) showed an increased intracellular ROS levels and enhanced nuclear accumulation of Nrf2 protein. UCB stimulated transcriptional induction of ARE-GFP reporter gene and induced mRNA expression of multiple antioxidant response genes as: xCT, Gly1, γGCL-m, γGCL-c, HO-1, NQO1, FTH, ME1, and ATF3. Nrf2 siRNA decreased UCB induced mRNA expression of HO1 (75%), NQO1 (54%), and FTH (40%). The Nrf2-related HO-1 induction was reduced to 60% in cells pre-treated with antioxidant (NAC) or specific signaling pathway inhibitors for PKC, P38α and MEK1/2 (80, 40 and 25%, respectively). In conclusion, we demonstrated that SH-SY5Y cells undergo an adaptive response against UCB-mediated oxidative stress by activation of multiple antioxidant response, in part through Nrf2 pathway.

Authors+Show Affiliations

Fondazione Italiana Fegato ONLUS, Italian Liver Foundation ONLUS, Bldg Q AREA Science Park - Basovizza Campus, 34149 Trieste, Italy. Electronic address: m.qaisiya@csf.units.it.Fondazione Italiana Fegato ONLUS, Italian Liver Foundation ONLUS, Bldg Q AREA Science Park - Basovizza Campus, 34149 Trieste, Italy. Electronic address: carlos.zabetta@csf.units.it.Fondazione Italiana Fegato ONLUS, Italian Liver Foundation ONLUS, Bldg Q AREA Science Park - Basovizza Campus, 34149 Trieste, Italy. Electronic address: cristina.bellarosa@csf.units.it.Fondazione Italiana Fegato ONLUS, Italian Liver Foundation ONLUS, Bldg Q AREA Science Park - Basovizza Campus, 34149 Trieste, Italy; Department of Medical Sciences, University of Trieste, 34100 Trieste, Italy. Electronic address: ctliver@csf.units.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24308969

Citation

Qaisiya, Mohammed, et al. "Bilirubin Mediated Oxidative Stress Involves Antioxidant Response Activation Via Nrf2 Pathway." Cellular Signalling, vol. 26, no. 3, 2014, pp. 512-20.
Qaisiya M, Coda Zabetta CD, Bellarosa C, et al. Bilirubin mediated oxidative stress involves antioxidant response activation via Nrf2 pathway. Cell Signal. 2014;26(3):512-20.
Qaisiya, M., Coda Zabetta, C. D., Bellarosa, C., & Tiribelli, C. (2014). Bilirubin mediated oxidative stress involves antioxidant response activation via Nrf2 pathway. Cellular Signalling, 26(3), 512-20. https://doi.org/10.1016/j.cellsig.2013.11.029
Qaisiya M, et al. Bilirubin Mediated Oxidative Stress Involves Antioxidant Response Activation Via Nrf2 Pathway. Cell Signal. 2014;26(3):512-20. PubMed PMID: 24308969.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bilirubin mediated oxidative stress involves antioxidant response activation via Nrf2 pathway. AU - Qaisiya,Mohammed, AU - Coda Zabetta,Carlos Daniel, AU - Bellarosa,Cristina, AU - Tiribelli,Claudio, Y1 - 2013/12/02/ PY - 2013/10/24/received PY - 2013/11/21/revised PY - 2013/11/26/accepted PY - 2013/12/7/entrez PY - 2013/12/7/pubmed PY - 2014/10/2/medline KW - ARE KW - ATF3 KW - Antioxidant Response Element KW - Bf KW - Bilirubin neurotoxicity KW - FTH KW - GSH KW - Gly1 KW - HO-1 KW - Heme oxygenase 1 KW - JNK KW - MAPK KW - ME1 KW - N-acetylcystein KW - NAC KW - NADPH quinone oxidoreductase 1 KW - NF-E2 related factor 2 KW - NQO1 KW - Nrf2 KW - Nrf2 pathway KW - OS KW - Oxidative stress KW - PERK KW - PI3K KW - PKC KW - ROS KW - Stress response protein kinases KW - UCB KW - activating transcription factor 3 KW - c-Jun NH2-terminal kinases KW - cystine/glutamate exchanger system KW - cytosolic malic enzyme 1 KW - eIF2α KW - eukaryotic translation initiation factor 2α KW - ferritin heavy chain KW - free bilirubin KW - glutathione KW - glycine up-take transporter KW - heme oxygenase 1 KW - mitogen-activated protein kinase KW - oxidative stress KW - phosphatidylinositide 3-kinases KW - protein kinase C KW - protein kinase-like endoplasmic reticulum kinase KW - reactive oxygen species KW - tBHQ KW - tertiary-butylhydroquinone KW - unconjugated bilirubin KW - xCT KW - γ-GCL-c KW - γ-GCL-m KW - γ-glutamylcysteine synthetase, catalytic subunit KW - γ-glutamylcysteine synthetase, modulatory subunit SP - 512 EP - 20 JF - Cellular signalling JO - Cell. Signal. VL - 26 IS - 3 N2 - Unconjugated bilirubin (UCB) is responsible for neonatal jaundice and high level of free bilirubin (Bf) can lead to kernicterus. Previous studies suggest that oxidative stress is a critical component of UCB-induced neurotoxicity. The Nrf2 pathway is a powerful sensor for cellular redox state and is activated directly by oxidative stress and/or indirectly by stress response protein kinases. Activated Nrf2 translocates to nucleus, binds to Antioxidant Response Element (ARE), and enhances the up-regulation of cytoprotective genes that mediate cell survival. The aim of the present study was to investigate the role of Nrf2 pathway in cell response to bilirubin mediated oxidative stress in the neuroblastoma SH-SY5Y cell line. Cells exposed to a toxic concentration of UCB (140 nM Bf) showed an increased intracellular ROS levels and enhanced nuclear accumulation of Nrf2 protein. UCB stimulated transcriptional induction of ARE-GFP reporter gene and induced mRNA expression of multiple antioxidant response genes as: xCT, Gly1, γGCL-m, γGCL-c, HO-1, NQO1, FTH, ME1, and ATF3. Nrf2 siRNA decreased UCB induced mRNA expression of HO1 (75%), NQO1 (54%), and FTH (40%). The Nrf2-related HO-1 induction was reduced to 60% in cells pre-treated with antioxidant (NAC) or specific signaling pathway inhibitors for PKC, P38α and MEK1/2 (80, 40 and 25%, respectively). In conclusion, we demonstrated that SH-SY5Y cells undergo an adaptive response against UCB-mediated oxidative stress by activation of multiple antioxidant response, in part through Nrf2 pathway. SN - 1873-3913 UR - https://www.unboundmedicine.com/medline/citation/24308969/Bilirubin_mediated_oxidative_stress_involves_antioxidant_response_activation_via_Nrf2_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0898-6568(13)00360-4 DB - PRIME DP - Unbound Medicine ER -