Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/52273
標題: 甘草甜素與甘草次酸之抗發炎作用評估與其對 PI3K 和糖皮質激素受器之交互作用研究
Anti-inflammatory abilities of glycyrrhizic acid and 18β-glycyrrhetinic acid and their effects on the interaction between PI3K and glucocorticoid receptor
作者: 高滋鍵
Kao, Tzu-Chien
關鍵字: 甘草次酸;glycyrrhizic acid;磷脂醯肌醇三激酶;糖皮質激素受器;抗發炎;糖皮質激素阻抗;抗氧化;glycyrrhetinic acid;phosphoinositide 3-kinase;glucocorticoid receptor;anti-inflammation;glucocorticoid resistance;anti-oxidation
出版社: 食品暨應用生物科技學系所
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摘要: 
甘草 (licorice) 為中藥中常見之藥材,廣泛被應用於肺部相關疾患。其中之甘草甜素 (glycyrrhizic acid, GA) 與甘草次酸 (18β-glycyrrhetinic acid, 18βGA),雖已證實可能有抗發炎功效,但詳細之機轉目前尚無詳盡之研究。本研究將由傳統抗發炎之角度切入,釐清甘草中的主要成分甘草甜素與甘草次酸之是否具有抗發炎效應與其可能機制,並進一步分析甘草甜素與甘草次酸於發炎細胞內對於各類訊息傳導蛋白質表現之影響。最後則進行甘草甜素與甘草次酸之功能性分析,探討其對於細胞內各種轉錄因子之影響,並了解其是否能緩解糖皮質激素阻抗,並探討其可能之分子機轉。

肺部疾患如氣喘及慢性阻塞性肺炎等,都是由發炎所誘發。甘草於中醫應用中即用來治療肺部疾患,甘草甜素為甘草中之主要活性成分,其在部份研究中也證實可減緩與發炎反應相關之肺部疾病。於先前之研究中,甘草中的甘草甜素與甘草次酸可藉由活化 PI3K/Akt 路徑達到保護神經細胞之效果。因甘草甜素與甘草次酸之抗發炎效果仍未被確立,故探討甘草甜素與甘草次酸之抗發炎效應與其可能機轉。實驗顯示,甘草甜素可透過 PI3K/Akt/GSK3β 路徑達到抗發炎之效果;而甘草次酸則可增進糖皮質激素受器 (glucocorticoid receptor, GR) 與其抑制蛋白 heat shock protein 90 (HSP90) 之解離,進而抑制發炎反應。這些結果顯示,甘草甜素與甘草次酸可透過不同之機轉達到抗發炎之效。由本實驗可推知,甘草甜素與甘草次酸可作為肺部發炎之有效抗發炎劑。

甘草具有之抗發炎能力已經為不爭之事實,但其機轉除抗菌外,其餘細胞內之分子機轉則尚未被釐清。於先前研究中證實,甘草中的主要活性成分甘草甜素 (glycyrrhizic acid, GA) 與其代謝物甘草次酸 (18β-glycyrrhetinic acid, 18βGA),可透過調控細胞內 PI3K 與糖皮質激素受器 (glucocorticoid receptor, GR),進而達到抑制 LPS 誘導之發炎反應。但其中所牽涉之細胞內機轉之變化,目前尚未有詳盡之探討。為瞭解甘草甜素與甘草次酸如何影響細胞內蛋白質間交互作用,故選擇以蛋白質體學之方式進行後續之研究。由 2-DE 結果可知,LPS 與 RAW264.7 細胞共同培養 1 小時後,即觀察到 3 個蛋白質分子表現量顯著受到影響,這些蛋白質為 coronin-1A (表現量下降)、ribose-phosphate pyrophosphokinase 1 (表現量上升) 與 calcyclin-binding protein (表現量上升)。而甘草甜素或甘草次酸與 LPS 一同與 RAW264.7 細胞共同培養後,可造成多種蛋白質分子表現量之顯著下降,這些蛋白質與細胞骨架 (coronin-1A and actin-related protein 3)、受器調控 (peptidyl-prolyl cis-trans isomerase FKBP4 及 heterogeneous nuclear ribonucleoprotein H/F)、核酸調節 (ribose-phosphate pyrophosphokinase 1)、泛素系統 (calcyclin-binding protein)、能量代謝 (alpha-enolase) 與氧化壓力 (T-complex protein 1、UPF0160 protein MYG1 (mitochondrial) 與 cytochrome b-c1 complex subunit 1 (mitochondrial)) 之指標息息相關。因觀察到諸多細胞內能量代謝相關之蛋白質表現改變,且 ATP 於發炎反應中為促進之角色,故進一步觀察細胞內能量代謝之情形。結果顯示甘草甜素與甘草次酸可增加細胞內 ATP 之產生,但甘草次酸於 50 μM 之濃度則出現顯著抑制之情形。由此可知,甘草甜素與甘草次酸可影響 LPS 誘導後細胞中多種蛋白質表現量如ribose-phosphate pyrophosphokinase 1 與 peptidyl-prolyl cis-trans isomerase FKBP4,藉此達到調節細胞內功能與發炎之作用。而這些作用也許與細胞內 ATP 相關之調控因子有一定之相關性,可作為未來研究之目標。

糖皮質激素 (glucocorticoids) 為臨床上常用於治療發炎性疾病,如氣喘 (asthma) 及慢性阻塞性肺炎 (chronic obstructive pulmonary disease)。近年來,越來越多之患者顯現出糖皮質激素阻抗 (glucocorticoid resistance) 之現象,成為臨床治療上之重要課題。在這些病患上,以額外之處理回復糖皮質激素之敏感性,似乎是可行之治療方針。甘草為常用之中草藥,常用於治療咳嗽等症狀。其中甘草甜素與甘草次酸為中藥中甘草之主要生物活性成分,先前研究中顯示其具有抗發炎及提昇抗氧化能力之效。結果顯示,甘草甜素與甘草次酸可提昇 dual specificity protein phosphatase 1 (DUSP1) 之表現量,而糖皮質激素受器抑制劑 RU486 不影響其效果。甘草甜素與甘草次酸可透過啟動 PI3K 與糖皮質激素受器提昇 DUSP1 之表現,並一併活化下游轉錄因子如 AP1 (activator protein 1)、CRE (cAMP response element)、GRE (glucocorticoid receptor element) 與 NFAT (nuclear factor of activated T-cells)。為瞭解甘草甜素與甘草次酸是否具有回復糖皮質激素阻抗之效應,本研究嘗試以氧化壓力之觀點建立體外誘導糖皮質激素阻抗之細胞模式。在此模式下,甘草甜素與甘草次酸可透過增加 heme oxygenase 1 (HO-1) 回復因氧化壓力而被抑制之糖皮質激素受器敏感性。因降低氧化壓力,與糖皮質激素受器阻抗有關之 p38 與 nitric oxide (NO) 也同時受到抑制。該效應與甘草甜素與甘草次酸啟動之 PI3K 與下游轉錄因子之活化有一定之關聯性。

由本實驗結果可知,甘草內之甘草甜素與甘草次酸可抑制過度發炎反應,並能透過啟動細胞內多種轉錄因子,提升細胞內抗氧化系統與調節免疫系統。這些機轉之調控可應用於回復糖皮質激素敏感性;並對於保健食品與未來治療輔助用劑之開發,具良好之參考應用價值。

Licorice is used to treat inflammatory-related lung diseases in traditional Chinese medicine. Glycyrrhizic acid (GA) and 18β-glycyrrhetinic acid (18βGA) are bioactive compounds in licorice and their function about anti-inflammation has already been described, but the mechanisms except anti-becterial and anti-viral remain unclear. In this study, the anti-inflammatory abilities of GA and 18βGA and the mechanisms are evaluated. The protein-protein interactions which modulated by GA and 18βGA are studied by 2-DE. Finally, the biological functions of GA and 18βGA against the glucocorticoid resistance are also investigated.

Many lung-related diseases, such as asthma and chronic obstructive pulmonary disease, are initiated by airway inflammation, and several studies indicated that GA alleviates inflammatory lung disease. Previously study showed that GA and 18βGA, found in licorice, can act as neuroprotective agents by promoting downstream PI3K/Akt signaling. In this study, the effects of GA and 18βGA on inflammation were investigated. Both GA and 18βGA reduce inflammatory cytokine production and its resulting anti-inflammation. Glycyrrhizic acid acts via PI3K/Akt/GSK3β to reduce cytokine production, while 18β-glycyrrhetinic acid leads to the dissociation of a glucocorticoid receptor (GR)-HSP90 complex to block inflammation. These data suggest that GA and 18βGA display anti-inflammatory activities but inhibit inflammation via different mechanisms. Based on these evidence, GA and 18βGA may be valuable biological inhibitors of lung inflammation.

It is known that licorice can be used to remedy inflammation, but the detail mechanism remains unknown. Previous study confirmed that, glycyrrhizic acid (GA), the bioactive compound of licorice, and its metabolite 18β-glycyrrhetinic acid (18βGA) can inhibit LPS-induced inflammation by modulating PI3K and glucocorticoid receptor (GR). For understanding the protein-protein interactions affected by GA and 18βGA, 2-DE was applied to evaluate the detail mechanism mediated by GA and 18βGA in cells with inflammation. After co-incubated RAW264.7 cells with LPS, three protein expressions (coronin-1A (decreased), ribose-phosphate pyrophosphokinase 1 (increased) and calcyclin-binding protein (increased)) were significantly changed. More protein expressions were significantly decreased by incubated LPS-induced RAW264.7 cells with GA or 18βGA, and these proteins were related to cytoskeleton (coronin-1A and actin-related protein 3), receptor modulation (peptidyl-prolyl cis-trans isomerase FKBP4 and heterogeneous nuclear ribonucleoprotein H/F), ubiquitylation (calcyclin-binding protein), energy metabolism (alpha-enolase) and biological marker of oxidative stress (T-complex protein 1, UPF0160 protein MYG1 (mitochondrial) and cytochrome b-c1 complex subunit 1 (mitochondrial)). Furthermore, the ATP content was also evaluated because of many protein expressions were affected which were related to energy metabolism and it plays a role in promoting inflammation. Generally, GA and 18βGA could promote the ATP content in cells, but 18βGA could down-regulate it at concentration of 50 μM. This data indicate that GA and 18βGA could modulate many protein expressions, such as ribose-phosphate pyrophosphokinase 1 and peptidyl-prolyl cis-trans isomerase FKBP4, in order to regulate the cell function and inflammation by ATP-dependent pathways.

Glucocorticoids are widely used in the clinical setting as remedies for inflammatory diseases, such as asthma and chronic obstructive pulmonary disease. However, the constant increase in the number of patients suffering from glucocorticoid resistance could present a serious problem for clinicians. In these cases, it may be reasonable to use additional treatments to restore the therapeutic effect of glucocorticoids. Glycyrrhizic acid and 18β-glycyrrhetinic acid are bioactive compounds in licorice that have been used for thousands of years in traditional Chinese medicine to treat coughs. It is showed that GA and 18βGA exhibit potential anti-inflammatory and antioxidant properties. Glycyrrhizic acid and 18β-glycyrrhetinic acid induced dual specificity protein phosphatase 1 (DUSP1) expression, and this effect was unchanged by the addition of RU486, a GR antagonist. The stimulation of DUSP1 expression by GA and 18βGA occurred via both GR and PI3K signaling, and the simultaneous activation of transcription elements, such as AP1 (activator protein 1), CRE (cAMP response element), GRE (glucocorticoid receptor element) and NFAT (nuclear factor of activated T-cells), was confirmed. Furthermore, we designed an in vitro glucocorticoid resistance model to verify the effects of GA and 18βGA on glucocorticoid resistance that was induced by ROS. The data showed that these two phytochemicals restored glucocorticoid sensitivity by depleting reactive oxygen species (ROS) through HO-1 expression. p38 and NO, which are factors that are induced by ROS and caused depletion of GR signaling, were inhibited by GA and 18βGA treatment. This phenomenon was considered to be related to the coordinated modulation of GR and PI3K signaling by GA and 18βGA, in conjugation with AP1, CRE, GRE and NFAT activation.

This study shows GA and 18βGA in licorice can inhibit over-reacted inflammation and activate multiple transcription factors to elevate the antioxidant system and modulate immune system. These mechanisms may help to restore the glucocorticoid sensitivity, and can be applied in nutraceutical and medicine.
URI: http://hdl.handle.net/11455/52273
其他識別: U0005-2608201317204000
Appears in Collections:食品暨應用生物科技學系

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