Paeonia japonica ameliorates oxidative stress-induced liver injury through activation of AMPK-mediated GSK3β

Paeonia japonica root has been widely used in Korean traditional medicine for its anti-oxidative, anti-inflammatory, analgesic, and anti-spasmodic effects as well as anti-convulsant and anti-anxiety activities [1 – 4]. Arachidonic acid (AA) + iron induce apoptosis through excess production of reactive oxygen species and mitochondrial dysfunction [5]. In this study, we investigated the hepatoprotective effects of P. japonica root extract (PJE) and its molecular mechanisms involved. PJE protects HepG2 cells from AA + iron-induced hepatotoxicity in a dose-dependent manner. In addition, PJE attenuated H₂O₂ production and restored GSH depletion and mitochondrial dysfunction induced by AA + iron. Based on a previous study, it is known that AMPK and GSK3β are involved in hepatocytes protection from oxidative stress induced by AA + iron [6]. Results from immunoblot analysis showed that PJE significantly increased the phosphorylation of AMPK as well as GSK3β. Moreover, chemical inhibition of AMPK blocked the ability of PJE to increase inactive phosphorylation of GSK3β, indicating that AMPK is one of upstream kinase to regulate GSK3β. Furthermore, benzoic acid, albiflorin and paeoniflorin found in PJE contributed to cell protection through AMPK activation. To validate our knowledge that PJE protects cells from AA + iron in vitro, we used a phenylhydrazine-induced acute liver injury model. Oral administration of PJE showed remarkable hepatoprotective effects against phenylhydrazine-induced peripheral hepatic damage and alleviated nitrotyrosine and 4-HNE immunoreactivity in hepatic tissues. Thus, Paeonia japonica root might be a beneficial pharmaceutical material for the treatment of oxidative stress-mediated liver injuries.

Acknowledgements: This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (No. 2012 R1A5A2A42671316).

Keywords: Paeonia japonica, oxidative stress, AMPK, GSK3β.

References:

[1] Okubo T, Nagai F, Seto T, Satoh K, Ushiyama K, Kano I. The inhibition of phenyl-hydroquinone induced oxidative DNA cleavage by consituents of Moutan Cortex and Paeoniae Radix. Biol Pharm Bull 2000; 23:199 – 203

[2] Murakami N, Saka M, Shimada H, Matsuda H, Yamahara J, Yoshikawa M. New bioactive monoterpene glycosides from Paeoniae Radix. Chem Pharm Bull 1996; 44:1279 – 1281

[3] Lee SE, Hwang HJ, Ha JS, Jeong HS, Kim JH. Screening of medicinal plant extracts for antioxidant activity. Life Sci 2003; 73:167 – 179

[4] Nizami Q, Jafri MA. Anticonvulsant, antianxiety and memory enhancing activities of delphinium denudatum and Paeonia emodi. Eur Neuropharm 2005; 15:S638

[5] Shin SM, Kim SG. Inhibition of arachidonic acid and iron-induced mitochondrial dysfunction and apoptosis by oltipraz and novel 1,2-dithiole-3-thione congeners. Mol Pharmacol 2009; 75: 242 – 253

[6] Choi SH, Kim YW, Kim SG. AMPK-mediated GSK3beta inhibition by isoliquiritigenin contributes to protecting mitochondria against iron-catalyzed oxidative stress. Biochem Pharmacol 2010; 79:1352 – 1362

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