香杉芝和AC-0抗發炎與抗動脈粥狀硬化機制探討

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香杉芝和AC-0抗發炎與抗動脈粥狀硬化機制探討

The mechanism of the anti-inflammatory and anti-atherosclerosis effect from Antrodia Salmonea and AC-0

林書緯 , Masters　　Advisor：楊新玲　　Co-advisor ：許游章

繁體中文

香杉芝； AC-0 ；抗氧化；抗發炎；抗動脈粥狀硬化； Antrodia Salmonea ； AC-0 ； antioxidant ； anti-inflammatory ； anti-atherosclerosis

Abstract │ Reference (176) │ Times Cited (2) │ Altmetrics

Abstract 〈TOP〉

發炎是身體抵抗外來微生物侵略的防禦反應，但長時間發炎反應對人體有害且會導致疾病的發生，例如：動脈粥狀硬化、癌症…等的病程發展有密切關係。如何增強體內抗氧化防禦能力，降低發炎反應成了預防醫學的重要課題。本實驗室先前已經證實香杉芝 (Antrodia Salmonea, AS) 和AC-0具有抗癌的效果，但對抗發炎活性與機制尚未明瞭，本研究利用巨噬細胞、小鼠體內試驗與內皮細胞三種模式詳盡的探討AS和AC-0，是否可以增加體內抗氧化防禦系統，抑制發炎反應及動脈粥狀硬化的發生。
本研究得知AS在巨噬細胞中可以透過MAPK和PI3K路徑活化Nrf2，促使Nrf2入核表現、增加ARE啟動子活性，使下游抗氧化酵素HO-1、NQO-1、γ-GCLC和GSH增加表現。增加抗氧化酵素表現具有清除LPS所大量誘導ROS能力，而抑制AP-1 family (c-fos和c-Jun) 入核表現，進而抑制發炎蛋白質COX-2與iNOS表現以及細胞激素NO、PGE2、TNF-α和IL-1β的分泌，而達到抗發炎功效；在LPS誘導小鼠腹膜炎模式中，AS可以有效降低血清TNF-α與IL-1β量，並且可以降低肝脾發炎相關蛋白質表現，包括TNF-α、IL-1β、COX-2、iNOS和NF-κB p65，並提升Nrf2的表現，具有抗發炎的生理活性；而在內皮細胞中也可以有效促進Nrf2入核表現，增加ARE啟動子活性，使下游抗氧化酵素HO-1、γ-GCLC和GSH的生成。當細胞受到TNF-α刺激誘導動脈粥狀硬化時，AS可以有效的透過抗氧化酵素降低NF-κB路徑活化，降低黏附因子ICAM-1以及MMP-9，抑制內皮細胞黏附作用，達到抗動脈粥狀硬化的效果。
另外，AC-0在巨噬細胞中可以透過ROS-JNK路徑活化Nrf2，降低Keap1對Nrf2的鉗制並減少Nrf2泛素化標定，促使Nrf2活化入核表現、增加ARE啟動子活性，使下游抗氧化酵素HO-1、NQO-1和GSH增加表現。增加抗氧化酵素表現具有清除LPS所大量誘導ROS能力，而抑制NF-κB和AP-1 family入核表現以及其啟動子活性，進而抑制發炎蛋白質COX-2與iNOS表現以及細胞激素NO、PGE2、TNF-α和IL-1β的分泌，而達到抗發炎功效；在LPS誘導小鼠腹膜炎模式中，AC-0可以有效降低血清TNF-α與IL-1β量，並且可以降低肝脾發炎相關蛋白質表現，包括TNF-α、IL-1β、COX-2、iNOS和NF-κB p65，並提升Nrf2的表現，具有抗發炎的生理活性；而在內皮細胞中也可以有效促進Nrf2入核表現，增加ARE啟動子活性，使下游抗氧化酵素HO-1、γ-GCLC和GSH的生成。當細胞受到TNF-α刺激誘導動脈粥狀硬化時，AC-0可以有效的透過抗氧化酵素降低NF-κB路徑活化，降低黏附因子ICAM-1以及MMP-9，抑制內皮細胞黏附作用，達到抗動脈粥狀硬化的效果。
本研究證明AS和AC-0不論在巨噬細胞或內皮細胞中，皆可以有效提升抗氧化酵素的表現。並且在體內外皆具有良好抗LPS所誘導發炎反應的活性；AS和AC-0也具抑制TNF-α誘導內皮細胞動脈粥狀硬化的作用。而AS和AC-0抗發炎與抗動脈粥狀硬化的效果都與提升抗氧化酵素有正相關性。這些結果希望有助於人類預防或減緩發炎反應造成的動脈粥狀硬化、心血管疾病或癌症等疾病，並且做為開發機能性保健食品的依據。

Parallel Abstract 〈TOP〉

The present study is conducted to investigate the antioxidant and anti-inflammatory potential of Antrodia Salmonea (AS) and AC-0. Our previous studies have demonstrated that AS and AC-0 exerted anti-cancer effects, however the anti-inflammatory activity and their underlying molecular mechanism are poorly understood. In this study, we investigated the anti-oxidant, anti-inflammation and anti-atherosclerotic effects of AS and AC-0 in vitro and in vivo. 
Treatment of AS and AC-0 caused a significant increase in anti-oxidant genes including HO-1, NQO-1, γ-GCLC and GSH expression in RAW 264.7 macrophage and EA.hy 926 endothelial cells. In addition, AS and AC-0 significantly increased the transcriptional activity of Nrf2, which transcribe HO-1, NQO-1, γ-GCLC and GSH genes. The AS and AC-0-induced Nrf2 activation was mediated by the nuclear translocation and binding with ARE followed by the disassociation of Keap-1/Nrf2 complex. These data indicates that the anti-oxidant potential of AS and AC-0 is mediated by the augmentation of anti-oxidant genes by Nrf2 signaling pathway.
Next, we examined the anti-inflammatory potential of AS and AC-0 in vitro. Results showed that treatment with AS and AC-0 significantly inhibited the production NO, PGE2, TNF-α and IL-1β in LPS-stimulated RAW 264.7 macrophage cells. Consistent with these observations, the expression of iNOS and COX-2 also inhibited by AS and AC-0 in a dose-dependent manner at both transcriptional and translational levels. In addition, AC-0 reduced the LPS-induced NF-κB and AP-1 transcriptional activity by suppressing the nuclear translocation and its promoter activity, whereas treatment of AS only inhibited the AP-1 transcriptional activity, but not affects the NF-κB. In Nrf2 knockdown cells, AS and AC-0-induced inhibition of NO, PGE2, TNF-α and IL-1β production were significantly reversed. Taken together, these data suggest that the anti-inflammatory potential of AS and AC-0 is dependents on their antioxidant activity. Further to confirm the anti-inflammatory activity of AS and AC-0 in vivo studies were performed. The LPS-induced secretion of TNF-α and IL-β in the serum was significantly inhibited by AS and AC-0 in a dose-dependent manner.  Results of immunohistochemistry analyses revealed that the LPS-induced expression of inflammatory proteins including TNF-α, IL-1β, COX-2, iNOS and NF-κB p65 in the liver and spleen were significantly down-regulated by AS and AC-0. Notably, AS and AC-0 treatment also significantly enhanced Nrf2 expression in liver and spleen. These results suggest that AS and AC-0 could be potential agents for inflammatory disorders. 
Further, we investigates the anti-atherosclerotic activity of AS and AC-0 in TNF-α-induced  EA.hy 926 endothelial cells. Treatment of AS and AC-0 significantly inhibited the adhesion of U937 to EA.hy 926 cells in a dose-dependent manner. AS and AC-0 also down-regulates TNF-α-induced ICAM-1 protein and mRNA expression. In addition, AS and AC-0 reduced TNF-α-induced migration, invasion, tube formation ability and MMP-9 activity and expression, which are the major atherosclerotic factors. Furthermore, AS and AC-0 suppressed TNF-α-induced IKK activation and NF-κB transcriptional activity in EA.hy 926 cells. Interestingly, in HO-1 knockdown cell line, AS and AC-0-induced inhibition of cellular adhesion, invasion and tube formation were reversed. These data suggest that the anti-atherosclerotic potential of AS and AC-0 is dependents on their antioxidant activity.

Reference ( 176 ) 〈TOP〉

5. Shen, C., et al., New lanostanes and naphthoquinones isolated from Antrodia salmonea and their antioxidative burst activity in human leukocytes. Planta Medica, 2006. 72(3): p. 199-203.
連結：
6. Shen, C., et al., Anti-inflammatory ergostanes from the basidiomata of Antrodia salmonea. Planta Medica, 2007. 73(11): p. 1208-13.
連結：
7. Huang, G.J., et al., Anti-inflammatory effects of ethanolic extract of Antrodia salmonea in the lipopolysaccharide-stimulated RAW246.7 macrophages and the lambda-carrageenan-induced paw edema model. Food and Chemical Toxicology, 2012. 50(5): p. 1485-1493.
連結：
8. Wang, L.T., Composition, taste quality and biological activities of extracts from mycelia of Antrodia salmonea. Master thesis, 2011.
連結：
12. Hsiao, G., et al., Antioxidative and hepatoprotective effects of Antrodia camphorata extract. J Agric Food Chem, 2003. 51(11): p. 3302-8.
連結：

Times Cited (2) 〈TOP〉

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