Anti-oxidative stress effect of red ginseng in the brain is mediated by peptidyl arginine deiminase type IV (PADI4) repression via estrogen receptor (ER) beta up-regulation

作者：Kim Eun Hye; Kim In Hye; Lee Mi Jeong; Cuong Thach Nguyen; Ha Jung Ah; Lee Soo Cheol; Choi Sangdun; Choi Kwang Tae; Pyo Suhkneung; Rhee Dong Kwon^*

来源：Journal of Ethnopharmacology, 2013, 148(2): 474-485.

DOI：10.1016/j.jep.2013.04.041

• Panax ginseng
• Immobilization (IMO)
• Oxidative stress
• Peptidyl arginine deiminase type 4 (PADI4)
• Estrogen receptor-beta (ER-beta)
• Apoptosis

Aim of the study: Ginseng has been used as an anti-stress agent, and its active ingredient, ginsenoside, is similar in structure to estrogen. However, the effect of ginseng on the stressed brain is not completely understood. The aim of this study is to understand systematically how red ginseng (RG) affects gene expressions in the brain of immobilization (IMO) stressed mice to elucidate its underlying mechanism. %26lt;br%26gt;Materials and methods: For in vivo experiments, mice were stressed by immobilization for 30, 45, or 60 min, and gene expression in the mice brain was analyzed by microarray and system biology. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling (TUNEL) staining, and gene expression by Western blot or qPCR. For in vitro study, the SK-N-SH neuroblastoma cells were stressed by H2O2 exposure. The resultant cytotoxicity was measured by MTF assay, and gene expression by Western blot, ELISA, or qPCR. %26lt;br%26gt;Results: Microarray analysis of genes in IMO stressed mice brains showed that RG administration prior to IMO stress downregulated %26gt; 40 genes including peptidyl arginine deiminase type 4 (PADI4). Interestingly, PADI4 was up-regulated by various stresses such as H2O2, acrylamide, and tunicamycin in neuroblastoma SK-N-SH cells but inhibited by RG. IMO stress and in vitro H2O2 stress depressed the estrogen receptor (ER)-beta expression but not ER. However, RG treatment increased ERp expression both in vivo and in vitro. Comparative analysis regarding the networks by systems biology revealed that INF-alpha plays a critical role in IMO stress, and the cell death associated network was much higher than other categories. Consistently, the IMO stress induced INF-alpha and Cox-2 expressions, malondialdehyde (MDA), and cell death in the brain, whereas RG administration inhibited these inductions in vivo. siRNA and transient expression studies revealed that ER beta inhibited the PADI4 expression. %26lt;br%26gt;Conclusion: PADI4 could be used as an oxidative stress marker. RG seems to inhibit oxidative stress-inducible PADI4 by up-regulating ER beta expression in the brain thus protecting brain cells from apoptosis.

• 出版日期2013-7-9