Anti-Inflammatory Compounds from Atractylodes macrocephala.

In relation to anti-inflammatory agents from medicinal plants, we have isolated three compounds from Atractylodes macrocephala; 1, 2-[(2E)-3,7-dimethyl-2,6-octadienyl]-6-methyl-2, 5-cyclohexadiene-1, 4-dione; 2, 1-acetoxy-tetradeca-6E,12E-diene-8, 10-diyne-3-ol; 3, 1,3-diacetoxy-tetradeca-6E, 12E-diene-8, 10-diyne. Compounds 1-3 showed concentration-dependent inhibitory effects on production of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Western blotting and RT-PCR analyses demonstrated that compounds 1-3 suppressed the protein and mRNA levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, compounds 1-3 inhibited transcriptional activity of nuclear factor-κB (NF-κB) and nuclear translocation of NF-κB in LPS-activated RAW 264.7 cells. The most active compound among them, compound 1, could reduce the mRNA levels of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and suppress the phosphorylation of MAPK including p38, JNK, and ERK1/2. Taken together, these results suggest that compounds 1-3 from A. macrocephala can be therapeutic candidates to treat inflammatory diseases.

Stilbenoids from Rheum undulatum Protect Hepatocytes Against Oxidative Stress Through AMPK Activation.

Oxidative stress promotes several diseases, including liver disease. We have isolated several stilbenoids from Rheum undulatum to investigate their hepatoprotective activities and mechanism. Stilbenoids from R. undulatum protects hepatocytes against arachidonic acid + iron (AA + Fe) induced oxidative stress. Pterostilbene (compound 5) shows stronger activity than the others. Trimethoxystilbenoid (compound 6) shows best activity on protection of HepG2 cells from AA + Fe-induced oxidative stress, and trans-stilbenoid (compound 7) shows weak activity. These stilbenoids suppress ROS generation in AA + Fe-treated HepG2 cells and also suppress AA + Fe-induced MMP disruption. Their protective effects on AA + Fe-induced MMP disruption were abrogated by treatment of AMP-activated protein kinase (AMPK) inhibitor, compound C or transfection of dominant negative form of AMPK. Taken together, stilbenoids from R. undulatum protect hepatocytes against AA + Fe-induced oxidative stress through AMPK activation. And the methoxy groups in the aryl groups are important for their cytoprotective activity.

Inhibition of Wnt/ß-Catenin Pathway by Dehydrocostus Lactone and Costunolide in Colon Cancer Cells.

Abnormal activation of ß-catenin has been reported in 90% in the sporadic and hereditary colorectal cancer. The suppression of abnormally activated ß-catenin is one of the good strategies for chemoprevention and treatment of colorectal cancer. In this study, we have isolated two main compounds from root of Saussurea lappa, dehydrocostus lactone (DCL) and costunolide (CL), and investigated their anti-colorectal cancer activities. DCL and CL suppressed cyclin D1 and survivin through inhibiting nuclear translocation of ß-catenin. They also suppressed the nuclear translocation of galectin-3 that is one of the coactivators of ß-catenin in SW-480 colon cancer cells. Furthermore, DCL and CL suppressed proliferation and survival of SW-480 colon cancer cells through the induction of cell cycle arrest and cell death. Taken together, DCL and CL from root of S. lappa have anti-colorectal cancer activities through inhibiting Wnt/ß-catenin pathway.

In vitro neuroprotective activity of sesquiterpenoids from the flower buds of Tussilago farfara.

We have isolated four sesquiterpenoids from Tussilago farfara, a traditional herbal medicine in Korea and China, and investigated the protective effects on LPS-induced neuronal cell death. Four sesquiterpenoids inhibited the production of nitric oxide, prostaglandin E2 and tumor necrosis factor-α in LPS-treated BV-2 cells through the inhibition of NF-κB pathway. These sesquiterpenoids also inhibited reactive oxygen species (ROS) generation in LPS-treated BV-2 cells. Furthermore, they inhibited LPS-induced neuronal cell death in co-culture system through the inhibition of NF-κB pathway and scavenging of ROS. These results indicated that sesquiterpenoids from Tussilago farfara may have beneficial therapeutic potential for the treatment of neurodegenerative diseases through inhibition of microglial activation.

Red ginseng abrogates oxidative stress via mitochondria protection mediated by LKB1-AMPK pathway.

BACKGROUND: Korean ginseng (Panax ginseng C.A. Meyer) has been used as a botanical medicine throughout the history of Asian traditional Oriental medicine. Formulated red ginseng (one form of Korean ginseng) has been shown to have antioxidant and chemopreventive effects. METHODS: This study investigated the cytoprotective effects and mechanism of action of Korean red ginseng extract (RGE) against severe ROS production and mitochondrial impairment in a cytotoxic cell model induced by AA + iron. RESULTS: RGE protected HepG2 cells from AA + iron-induced cytotoxicity by preventing the induction of mitochondrial dysfunction and apoptosis. Moreover, AA + iron-induced production of ROS and reduction of cellular GSH content (an important cellular defense mechanism) were remarkably attenuated by treatment with RGE. At the molecular level, treatment with RGE activated LKB1-dependent AMP-activated protein kinase (AMPK), which in turn led to increased cell survival. The AMPK pathway was confirmed to play an essential role as the effects of RGE on mitochondrial membrane potential were reversed upon treatment with compound C, an AMPK inhibitor. CONCLUSIONS: Our results demonstrate that RGE has the ability to protect cells from AA + iron-induced ROS production and mitochondrial impairment through AMPK activation.

Heat shock increases expression of NAD(P)H:quinone oxidoreductase (NQO1), mediator of beta-lapachone cytotoxicity, by increasing NQO1 gene activity and via Hsp70-mediated stabilisation of NQO1 protein.

NAD(P)H:quinone oxidoreductase (NQO1) mediates cell death caused by the novel anti-cancer drug beta-lapachone (beta-lap). Therefore, beta-lap sensitivity of cells is positively related to the level of cellular NQO1. Heat shock up-regulates NQO1 expression in cancer cells, thereby enhancing the clonogenic cell death caused by beta-lap. The mechanisms by which heat shock elevates NQO1 expression were investigated in the present study using human A549 lung cancer cells and human MDA-MB-231 breast cancer cells. When MDA-MB-231(NQO1+) cells stably transfected with NQO1 were heated at 42 degrees C for 1 h the expression of NQO1 and the sensitivity of the cells to beta-lap progressively increased during the 24-48 h post-heating period. Heating increased NQO1 transcription by cis-acting elements such as xenobiotic response element and antioxidant response element located in the NQO1 gene promoter region. The turnover of NQO1 protein in heated cells was much slower than in unheated cells. NQO1 and heat shock protein 70 (Hsp70) co-precipitated and co-localised in cells before and after heating, demonstrating the close association of these two proteins in the cells. These results suggest that NQO1 is stabilised by the Hsp70 molecular chaperone. It is concluded that the prolonged increase in NQO1 expression after heat shock is due to increased NQO1 transcription, and also increased Hsp70-mediated NQO1 stabilisation.