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Isorhamnetin protects against oxidative stress by activating Nrf2 and inducing the expression of its target genes.
Toxicol Appl Pharmacol. 2014 Jan 15; 274(2):293-301.TA

Abstract

Isorhamentin is a 3'-O-methylated metabolite of quercetin, and has been reported to have anti-inflammatory and anti-proliferative effects. However, the effects of isorhamnetin on Nrf2 activation and on the expressions of its downstream genes in hepatocytes have not been elucidated. Here, we investigated whether isorhamnetin has the ability to activate Nrf2 and induce phase II antioxidant enzyme expression, and to determine the protective role of isorhamnetin on oxidative injury in hepatocytes. In HepG2 cells, isorhamnetin increased the nuclear translocation of Nrf2 in a dose- and time-dependent manner, and consistently, increased antioxidant response element (ARE) reporter gene activity and the protein levels of hemeoxygenase (HO-1) and of glutamate cysteine ligase (GCL), which resulted in intracellular GSH level increases. The specific role of Nrf2 in isorhamnetin-induced Nrf2 target gene expression was verified using an ARE-deletion mutant plasmid and Nrf2-knockout MEF cells. Deletion of the ARE in the promoter region of the sestrin2 gene, which is recently identified as the Nrf2 target gene by us, abolished the ability of isorhamnetin to increase luciferase activity. In addition, Nrf2 deficiency completely blocked the ability of isorhamnetin to induce HO-1 and GCL. Furthermore, isorhamnetin pretreatment blocked t-BHP-induced ROS production and reversed GSH depletion by t-BHP and consequently, due to reduced ROS levels, decreased t-BHP-induced cell death. In addition isorhamnetin increased ERK1/2, PKCδ and AMPK phosphorylation. Finally, we showed that Nrf2 deficiency blocked the ability of isorhamnetin to protect cells from injury induced by t-BHP. Taken together, our results demonstrate that isorhamnetin is efficacious in protecting hepatocytes against oxidative stress by Nrf2 activation and in inducing the expressions of its downstream genes.

Authors+Show Affiliations

College of Pharmacy, Chosun University, Gwangju, 501-759, Republic of Korea.College of Pharmacy, Chosun University, Gwangju, 501-759, Republic of Korea.College of Pharmacy, Chosun University, Gwangju, 501-759, Republic of Korea.College of Pharmacy, Chosun University, Gwangju, 501-759, Republic of Korea.College of Pharmacy, Chosun University, Gwangju, 501-759, Republic of Korea.Medical Research Center for Globalization of Herbal Formulation, College of Korean Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea.Medical Research Center for Globalization of Herbal Formulation, College of Korean Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea.Medical Research Center for Globalization of Herbal Formulation, College of Korean Medicine, Daegu Haany University, Gyeongsan 712-715, Republic of Korea.College of Pharmacy, Chosun University, Gwangju, 501-759, Republic of Korea.College of Pharmacy, Chosun University, Gwangju, 501-759, Republic of Korea. Electronic address: shki@chosun.ac.kr.

Pub Type(s)

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

Language

eng

PubMed ID

24211276

Citation

Yang, Ji Hye, et al. "Isorhamnetin Protects Against Oxidative Stress By Activating Nrf2 and Inducing the Expression of Its Target Genes." Toxicology and Applied Pharmacology, vol. 274, no. 2, 2014, pp. 293-301.
Yang JH, Shin BY, Han JY, et al. Isorhamnetin protects against oxidative stress by activating Nrf2 and inducing the expression of its target genes. Toxicol Appl Pharmacol. 2014;274(2):293-301.
Yang, J. H., Shin, B. Y., Han, J. Y., Kim, M. G., Wi, J. E., Kim, Y. W., Cho, I. J., Kim, S. C., Shin, S. M., & Ki, S. H. (2014). Isorhamnetin protects against oxidative stress by activating Nrf2 and inducing the expression of its target genes. Toxicology and Applied Pharmacology, 274(2), 293-301. https://doi.org/10.1016/j.taap.2013.10.026
Yang JH, et al. Isorhamnetin Protects Against Oxidative Stress By Activating Nrf2 and Inducing the Expression of Its Target Genes. Toxicol Appl Pharmacol. 2014 Jan 15;274(2):293-301. PubMed PMID: 24211276.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Isorhamnetin protects against oxidative stress by activating Nrf2 and inducing the expression of its target genes. AU - Yang,Ji Hye, AU - Shin,Bo Yeon, AU - Han,Jae Yun, AU - Kim,Mi Gwang, AU - Wi,Ji Eun, AU - Kim,Young Woo, AU - Cho,Il Je, AU - Kim,Sang Chan, AU - Shin,Sang Mi, AU - Ki,Sung Hwan, Y1 - 2013/11/07/ PY - 2013/08/12/received PY - 2013/10/24/revised PY - 2013/10/27/accepted PY - 2013/11/12/entrez PY - 2013/11/12/pubmed PY - 2014/3/4/medline KW - 5′ AMP-activated protein kinase KW - AMPK KW - ARE KW - Cytoprotection KW - ERK1/2 KW - GCS KW - HO-1 KW - Isorhamnetin KW - Methylated flavonoid KW - NAD(P)H:quinone reductase KW - NF-E2-related factor-2 KW - NQO1 KW - Nrf2 KW - PI3K KW - PKC KW - ROS KW - Sesn2 KW - antioxidant response element KW - extracellular signal-regulated kinase KW - hemeoxygenase 1 KW - phosphoinositide 3-kinase KW - protein kinase C KW - reactive oxygen species KW - sestrin2 KW - t-BHQ KW - tert-butylhydroquinone KW - γ-glutamylcysteine synthetase SP - 293 EP - 301 JF - Toxicology and applied pharmacology JO - Toxicol. Appl. Pharmacol. VL - 274 IS - 2 N2 - Isorhamentin is a 3'-O-methylated metabolite of quercetin, and has been reported to have anti-inflammatory and anti-proliferative effects. However, the effects of isorhamnetin on Nrf2 activation and on the expressions of its downstream genes in hepatocytes have not been elucidated. Here, we investigated whether isorhamnetin has the ability to activate Nrf2 and induce phase II antioxidant enzyme expression, and to determine the protective role of isorhamnetin on oxidative injury in hepatocytes. In HepG2 cells, isorhamnetin increased the nuclear translocation of Nrf2 in a dose- and time-dependent manner, and consistently, increased antioxidant response element (ARE) reporter gene activity and the protein levels of hemeoxygenase (HO-1) and of glutamate cysteine ligase (GCL), which resulted in intracellular GSH level increases. The specific role of Nrf2 in isorhamnetin-induced Nrf2 target gene expression was verified using an ARE-deletion mutant plasmid and Nrf2-knockout MEF cells. Deletion of the ARE in the promoter region of the sestrin2 gene, which is recently identified as the Nrf2 target gene by us, abolished the ability of isorhamnetin to increase luciferase activity. In addition, Nrf2 deficiency completely blocked the ability of isorhamnetin to induce HO-1 and GCL. Furthermore, isorhamnetin pretreatment blocked t-BHP-induced ROS production and reversed GSH depletion by t-BHP and consequently, due to reduced ROS levels, decreased t-BHP-induced cell death. In addition isorhamnetin increased ERK1/2, PKCδ and AMPK phosphorylation. Finally, we showed that Nrf2 deficiency blocked the ability of isorhamnetin to protect cells from injury induced by t-BHP. Taken together, our results demonstrate that isorhamnetin is efficacious in protecting hepatocytes against oxidative stress by Nrf2 activation and in inducing the expressions of its downstream genes. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/24211276/Isorhamnetin_protects_against_oxidative_stress_by_activating_Nrf2_and_inducing_the_expression_of_its_target_genes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(13)00474-2 DB - PRIME DP - Unbound Medicine ER -