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Stimulation of GSH synthesis to prevent oxidative stress-induced apoptosis by hydroxytyrosol in human retinal pigment epithelial cells: activation of Nrf2 and JNK-p62/SQSTM1 pathways.
J Nutr Biochem. 2012 Aug; 23(8):994-1006.JN

Abstract

The Nrf2-Keap1 pathway is believed to be a critical regulator of the phase II defense system against oxidative stress. By activation of Nrf2, cytoprotective genes such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase (NQO-1) and γ-glutamyl-cysteine ligase (GCL) are induced. GCL-induced glutathione (GSH) production is believed to affect redox signaling, cell proliferation and death. We here report that tert-butyl hydroperoxide (t-BHP)-induced GSH reduction led to mitochondrial membrane potential loss and apoptosis in cultured human retinal pigment epithelial cells from the ARPE-19 cell line. Hydroxytyrosol (HT), a natural phytochemical from olive leaves and oil, was found to induce phase II enzymes and GSH, thus protect t-BHP-induced mitochondrial dysfunction and apoptosis. Depletion of GSH by buthionine-[S,R]-sulfoximine enhanced t-BHP toxicity and abolished HT protection. Overexpression of Nrf2 increased GSH content and efficiently protected t-BHP-induced mitochondrial membrane potential loss. Meanwhile, HT-induced GSH enhancement and induction of Nrf2 target gene (GCLc, GCLm, HO-1, NQO-1) messenger RNA (mRNA) were inhibited by Nrf2 knockdown, suggesting that HT increases GSH through Nrf2 activation. In addition, we found that HT was able to activate the PI3/Akt and mTOR/p70S6-kinase pathways, both of which contribute to survival signaling in stressed cells. However, the effect of HT was not inhibited by the PI3K inhibitor LY294002. Rather, c-Jun N-terminal kinase (JNK) activation was found to induce p62/SQSTM1 expression, which is involved in Nrf2 activation. Our study demonstrates that Nrf2 activation induced by the JNK pathway plays an essential role in the mechanism behind HT's strengthening of the antiapoptotic actions of the endogenous antioxidant system.

Authors+Show Affiliations

College of Animal Sciences, Zhejiang University, Hangzhou, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

21937211

Citation

Zou, Xuan, et al. "Stimulation of GSH Synthesis to Prevent Oxidative Stress-induced Apoptosis By Hydroxytyrosol in Human Retinal Pigment Epithelial Cells: Activation of Nrf2 and JNK-p62/SQSTM1 Pathways." The Journal of Nutritional Biochemistry, vol. 23, no. 8, 2012, pp. 994-1006.
Zou X, Feng Z, Li Y, et al. Stimulation of GSH synthesis to prevent oxidative stress-induced apoptosis by hydroxytyrosol in human retinal pigment epithelial cells: activation of Nrf2 and JNK-p62/SQSTM1 pathways. J Nutr Biochem. 2012;23(8):994-1006.
Zou, X., Feng, Z., Li, Y., Wang, Y., Wertz, K., Weber, P., Fu, Y., & Liu, J. (2012). Stimulation of GSH synthesis to prevent oxidative stress-induced apoptosis by hydroxytyrosol in human retinal pigment epithelial cells: activation of Nrf2 and JNK-p62/SQSTM1 pathways. The Journal of Nutritional Biochemistry, 23(8), 994-1006. https://doi.org/10.1016/j.jnutbio.2011.05.006
Zou X, et al. Stimulation of GSH Synthesis to Prevent Oxidative Stress-induced Apoptosis By Hydroxytyrosol in Human Retinal Pigment Epithelial Cells: Activation of Nrf2 and JNK-p62/SQSTM1 Pathways. J Nutr Biochem. 2012;23(8):994-1006. PubMed PMID: 21937211.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Stimulation of GSH synthesis to prevent oxidative stress-induced apoptosis by hydroxytyrosol in human retinal pigment epithelial cells: activation of Nrf2 and JNK-p62/SQSTM1 pathways. AU - Zou,Xuan, AU - Feng,Zhihui, AU - Li,Yuan, AU - Wang,Ying, AU - Wertz,Karin, AU - Weber,Peter, AU - Fu,Yan, AU - Liu,Jiankang, Y1 - 2011/09/19/ PY - 2010/10/02/received PY - 2011/05/15/revised PY - 2011/05/16/accepted PY - 2011/9/23/entrez PY - 2011/9/23/pubmed PY - 2012/12/12/medline SP - 994 EP - 1006 JF - The Journal of nutritional biochemistry JO - J. Nutr. Biochem. VL - 23 IS - 8 N2 - The Nrf2-Keap1 pathway is believed to be a critical regulator of the phase II defense system against oxidative stress. By activation of Nrf2, cytoprotective genes such as heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase (NQO-1) and γ-glutamyl-cysteine ligase (GCL) are induced. GCL-induced glutathione (GSH) production is believed to affect redox signaling, cell proliferation and death. We here report that tert-butyl hydroperoxide (t-BHP)-induced GSH reduction led to mitochondrial membrane potential loss and apoptosis in cultured human retinal pigment epithelial cells from the ARPE-19 cell line. Hydroxytyrosol (HT), a natural phytochemical from olive leaves and oil, was found to induce phase II enzymes and GSH, thus protect t-BHP-induced mitochondrial dysfunction and apoptosis. Depletion of GSH by buthionine-[S,R]-sulfoximine enhanced t-BHP toxicity and abolished HT protection. Overexpression of Nrf2 increased GSH content and efficiently protected t-BHP-induced mitochondrial membrane potential loss. Meanwhile, HT-induced GSH enhancement and induction of Nrf2 target gene (GCLc, GCLm, HO-1, NQO-1) messenger RNA (mRNA) were inhibited by Nrf2 knockdown, suggesting that HT increases GSH through Nrf2 activation. In addition, we found that HT was able to activate the PI3/Akt and mTOR/p70S6-kinase pathways, both of which contribute to survival signaling in stressed cells. However, the effect of HT was not inhibited by the PI3K inhibitor LY294002. Rather, c-Jun N-terminal kinase (JNK) activation was found to induce p62/SQSTM1 expression, which is involved in Nrf2 activation. Our study demonstrates that Nrf2 activation induced by the JNK pathway plays an essential role in the mechanism behind HT's strengthening of the antiapoptotic actions of the endogenous antioxidant system. SN - 1873-4847 UR - https://www.unboundmedicine.com/medline/citation/21937211/Stimulation_of_GSH_synthesis_to_prevent_oxidative_stress_induced_apoptosis_by_hydroxytyrosol_in_human_retinal_pigment_epithelial_cells:_activation_of_Nrf2_and_JNK_p62/SQSTM1_pathways_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0955-2863(11)00154-9 DB - PRIME DP - Unbound Medicine ER -