臺灣博碩士論文加值系統

全文摘要

甘草 (licorice) 為傳統常用之藥用植物，屬多年生草本豆科植物 (Leguminosae) 之乾燥根及根莖，主產於內蒙古、新疆與東北等地。甘草含豐富之三萜類皂苷 (triterpenoid saponins)，最主要的活性成分為甘草甜素 (glycyrrhizic acid, GA) 及其水解產物甘草次酸 (18β-glycyrrhetinic acid, 18βGA)，具有抗氧化、抗發炎、抗菌、保護呼吸道與保護腎臟等功效，是極具發展潛力之素材。許多文獻指出氧化壓力 (oxidative stress) 與發炎反應 (inflammation) 在諸多疾病的發展過程中，扮演關鍵的角色，而補充天然植物性化合物 (phytochemicals) 後具有良好的預防效果。因此本實驗以脂多醣誘導性肺炎與化學性腎損傷等兩種動物模式，進行甘草甜素與甘草次酸體內生物活性之探討，依次為 (一) 甘草甜素與甘草次酸對細菌脂多醣誘導 BALB/c 小鼠急性肺損傷之影響與 (二) 甘草甜素與甘草次酸對順鉑誘導 BALB/c 小鼠腎毒性保護效應之探討。
首先以細菌脂多醣 (lipopolysaccharide, LPS) 誘導急性肺損傷 (acute lung injury, ALI)之動物模式，評估甘草甜素及甘草次酸對於 BALB/c 小鼠肺炎現象之改善效果，並以小鼠巨噬細胞株 RAW264.7 模擬甘草甜素與甘草次酸對呼吸道內巨噬細胞吞噬活性之影響。實驗結果顯示，以噴霧 (10 – 50 μg/mL) 或氣管滴注 (75 μg/mL) 等方式投予甘草甜素或甘草次酸，對細菌脂多醣所誘導之肺部發炎細胞激素 tumor necrosis factor-α (TNF-α)、interleukin-6 (IL-6) 及 interleukin-1 beta (IL-1β) 含量與噬中性白血球 (neutrophils) 於呼吸道內的蓄積，不具顯著抑制性；卻能顯著回復肺臟組織因細菌脂多醣傷害所降低之 catalase、superoxide dismutase (SOD)、glutathione reductase (GRd) 以及 glutathione S-transferase (GST) 等抗氧化酵素之活性 (p < 0.05)。細胞實驗結果顯示，給予 0.2 – 25 μM 之甘草甜素或甘草次酸，可使 RAW264.7 細胞對大腸桿菌 (Escherichia coli) 死菌顆粒的吞噬活性顯著上升 (p < 0.05)；而當濃度達 50 μM 時，兩種樣品則開始表現出抑制巨噬細胞吞噬活性之趨勢。因此，甘草甜素與甘草次酸雖無法抑制細菌脂多醣誘導所分泌發炎細胞激素，但能藉由提升抗氧化酵素活性及巨噬細胞吞噬活性，協助肺臟共同抵禦外來刺激因子。
以甘草甜素與甘草次酸具提升抗氧化防禦生物活性之現象為基礎，延伸至其他氧化性傷害疾病做進一步探討。以臨床化療藥物順鉑 (Cisplatin, CP) 誘導急性腎損傷 (acute kidney injury, AKI) 之動物模式，評估甘草甜素及甘草次酸對於緩解 BALB/c 小鼠腎毒性 (nephrotoxicity) 之保護效果。實驗結果顯示，甘草甜素與甘草次酸可顯著降低腎功能及組織傷害之血清指標blood urea nitrogen (BUN)、creatinine 及 lactate dehydrogenase (LDH) 數值 (p < 0.05)。病理分析發現，甘草甜素與甘草次酸可改善順鉑造成的腎小管壞死、阻塞及退化等腎臟組織病變。同時甘草甜素與甘草次酸亦可顯著回復腎臟組織於順鉑傷害下所降低的抗氧化相關酵素，如 catalase、SOD、GRd、GST、glutathione peroxidase (GPx) 之活性及 GSH/GSSG ratio，並顯著降低脂質過氧化產物 malondialdehyde (MDA) 之含量 (p < 0.05)。此外，於免疫組織染色 (immunohistochemical, IHC) 分析結果證實，甘草甜素與甘草次酸可調降促發炎轉錄因子 nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) 之表現與促發炎細胞激素 TNF-α、IL-1β、IL-6 及傷害相關分子 high-mobility group box 1 protein (HMGB1) 之釋放。同時可提升保護性蛋白 nuclear factor (erythroid-derived 2)-like 2 (Nrf2) 與 heme oxygenase-1 (HO-1) 之表現。綜合上述，甘草甜素與甘草次酸，可藉由提升抗氧化酵素活性與保護性蛋白表現，減少氧化傷害與發炎反應，有效維持腎功能並降低順鉑造成的腎毒性，因此有潛力作為緩解順鉑副作用之輔助劑。
歸納以上結果，證實甘草甜素與甘草次酸能透過提升免疫反應，並有效活化抗氧化防禦系統，進而抵禦生物性與化學性之組織傷害。本研究成果可做為甘草甜素與甘草次酸，應用於未來保健食品開發與臨床應用之參考依據。
關鍵字:甘草甜素、甘草次酸、細菌脂多醣、順鉑、抗氧化

Abstract

Licorice (Glycyrrhiza) species are perennial herbaceous Leguminosae plant, as traditional herbal medicine, and widely distributed in Inner Mongolia, Xinjiang and the Northeast of China. The pharmacological activities sush as antimicrobial, antioxidative, antiinflammatory, respiratory protective and renoprotective effects of licorice are mainly represented by main triterpenoid saponins, glycyrrhizic acid (GA) and its metabolite 18β-glycyrrhetinic acid (18βGA). Two kinds of animal model were used to evaluate the protective effects of lipopolysaccharide (LPS)-induced inflammation in lungs and chemical-induced renal toxicity. (A) The effects of GA and 18βGA on LPS-induced acute lung injury in BALB/c mice. (B) The protective roles of GA and 18βGA on cisplatin (CP)-induced nephrotoxicity in BALB/c mice.
The protective effects of GA and 18βGA on LPS-induced acute lung injury (ALI) in BALB/c mice were evaluated. The effects of GA and 18βGA on phagocytosis in RAW264.7 cells were also evaluated. Results showed that GA and 18βGA had no effects on tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β levels and neutrophil infiltration in mice airway. GA and 18βGA showed great potentials on upregulating activities of catalase, superoxide dismutase (SOD), glutathione reductase (GRd) and glutathione S-transferase (GST) which were inhibited by LPS treatment in mice lungs (p < 0.05). GA and 18βGA could promote phagocytic activity at 0.2 – 25 μM (p < 0.05) in RAW264.7 cells, but inhibit phagocytic activity above 50 μM. Taking together, neither GA nor 18βGA could inhibit inflammation, but GA and 18βGA would increase the activities of antioxidant enzymes and phagocytosis in order to remove the pathogenic materials and prevent further tissue damage.
Based on the properties, GA and 18βGA could improve oxidative damages through enhancement of antioxidant system. Therefore, this study also discussed the protective roles of GA and 18βGA on CP-induced nephrotoxicity. Results showed that pretreatment with GA or 18βGA significantly attenuated the CP-induced parameters such as serum blood urea nitrogen (BUN), creatinine and lactate dehydrogenase (LDH) (p < 0.05). The histopathological examinations also revealed the improvement of renal tubular necrosis, obstructive and degeneration by GA or 18βGA treatment. Moreover, GA and 18βGA prevented oxidative stress through significantly restoring the levels of antioxidant enzyme activities such as catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GRd), glutathione S-transferase (GST) and GSH/GSSG ratio, and decreasing lipid peroxidation marker malondialdehyde (MDA) in kidney tissues (p < 0.05). In addition, immunohistochemical examinations revealed that the expressions of pro-inflammatory transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), TNF-α, IL-1β, IL-6 and high-mobility group box 1 protein (HMGB1) were suppressed by GA or 18βGA treatment. The expressions of renal nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1) were up-regulated by GA or 18βGA treatment in CP-induced mice. Taking together, GA and 18βGA might be a potent protective agents through upregulation of protective proteins and antioxidant enzyme activities, which againsts renal oxidative and inflammatory damages caused by cisplatin.
In summary, these results confirmed that GA and 18βGA can enhance the immune response and through the activation of antioxidant defense system effectively, leading to avoid biological and chemical tissue damages. The results can be used in the development of funtional food and clinical application.
Keyword: glycyrrhizic acid, 18β-glycyrrhetinic acid, lipopolysaccharide, cisplatin, antioxidant

目次

全文摘要 I
Abstract III
目次 VI
圖次 IX
表次 XIII
縮寫表 XIV

前言 1
第一章、文獻整理 3
壹、肺損傷模式 4
一、肺臟與呼吸系統 4
二、急性肺損傷 (ALI) 與急性呼吸窘迫症候群 (ARDS) 6
三、先天免疫防禦. 9
四、巨噬細胞與免疫反應. 10
五、氧化傷害與抗氧化防禦.. 17
貳、腎損傷模式 23
一、腎臟與泌尿系統 23
二、急性腎損傷 (AKI) 24
三、順鉑 (cisplatin) 的臨床應用 28
四、順鉑之抗癌機制與腎毒性 29
參、樣品介紹 37
一、甘草 (Licorece) 37
二、甘草活性成分的相關研究 38
肆、研究目的 42
伍、研究架構 43


第二章、甘草甜素與甘草次酸對細菌脂多醣誘導 BALB/c 小鼠急性
肺損傷之影響 44
摘要 45
Abstract 47
前言 49
實驗架構 51
材料與方法 52
結果 59
一、甘草甜素及甘草次酸對細菌脂多醣誘導急性肺炎之 BALB/c
小鼠支氣管肺泡沖洗液 (BALF) 內發炎細胞激素之表現 59
二、甘草甜素及甘草次酸對細菌脂多醣誘導急性肺炎之 BALB/c
小鼠支氣管肺泡沖洗液 (BALF) 中白血球浸潤之影響 59
三、甘草甜素及甘草次酸對細菌脂多醣誘導急性肺炎之BALB/c
小鼠肺臟病理變化之影響 61
四、甘草甜素及甘草次酸對細菌脂多醣誘導急性肺炎之 BALB/c
小鼠肺臟抗氧化酵素活性之影響 61
五、甘草甜素及甘草次酸對 RAW264.7 細胞吞噬活性之影響 62
討論 64
第三章、甘草甜素與甘草次酸對順鉑誘導 BALB/c 小鼠腎毒性保護
效應之探討 83
摘要 84
Abstract 86
前言 88
實驗架構 90
材料與方法 91
結果 98
一、甘草甜素與甘草次酸對順鉑誘導 BALB/c 小鼠之腎功能評
估 98
二、甘草甜素與甘草次酸對順鉑誘導 BALB/c 小鼠腎臟組織病
理分析 98
三、甘草甜素與甘草次酸對順鉑誘導 BALB/c 小鼠腎臟抗氧化
相關酵素活性之影響 99
四、甘草甜素與甘草次酸對順鉑誘導 BALB/c 小鼠腎臟脂質過
氧化之影響 100
五、甘草甜素與甘草次酸對順鉑誘導 BALB/c 小鼠腎臟發炎相
關指標之影響 100
討論 102
總結論 137
參考文獻 139
 
圖次

圖 1-1、呼吸系統解剖構造圖 7
圖 1-2、正常肺泡與急性損傷肺泡比較圖 8
圖 1-3、細菌感染誘發的發炎反應 12
圖 1-4、細菌脂多醣分子結構圖 12
圖 1-5、細胞辨認脂多醣 13
圖 1-6、受巨噬細胞分泌之趨化激素與細胞激素調節，並與血管壁黏
附分子交互作用，使噬中性球由血液循環移動至發炎組織路
徑圖 16
圖 1-7、細胞內自由基產生與抗氧化酵素予以清除之交互作用 21
圖 1-8、細胞內抗氧化物質降低氧化壓力 22
圖 1-9、泌尿系統結構圖 25
圖 1-10、腎臟結構圖 26
圖 1-11、呼吸系統解剖構造圖 27
圖 1-12、順鉑與其他含鉑抗癌藥物結構圖 33
圖 1-13、順鉑進入細胞後的生物效應 (A) 及與 DNA 可能的交互連
結 (B) 34
圖 1-14、順鉑誘導腎毒性病理機制圖 35
圖 1-15、順鉑所活化的腎小管細胞凋亡路徑 36
圖 1-16、甘草及其切片圖 40
圖 1-17、甘草甜素與甘草次酸化學結構圖 41
圖 1-18、甘草甜素代謝圖 41
圖 2-1、噴霧系統 54
圖 2-2、動物實驗設計霧化吸入組 (A) 氣管滴注組 (B) 69
圖 2-3、甘草甜素與甘草次酸對細菌脂多醣誘導之霧化吸入組
BALB/c 小鼠BALF 中細胞激素 TNF-α、IL-6 與 IL-1β
之表現 70
圖 2-4、甘草甜素與甘草次酸對細菌脂多醣誘導肺炎之氣管滴注組
BALB/c 小鼠BALF 中細胞激素 TNF-α、IL-6 與 IL-1β
之表現 71
圖 2-5、甘草甜素與甘草次酸對細菌脂多醣誘導肺炎之霧化吸入組
BALB/c 小鼠BALF 中噬中性白血球之聚集 72
圖 2-6、甘草甜素與甘草次酸對細菌脂多醣誘導肺炎之氣管滴注組
BALB/c 小鼠BALF中噬中性白血球之聚集 73
圖 2-7、甘草甜素與甘草次酸對細菌脂多醣誘導肺炎之霧化吸入組
BALB/c 小鼠BALF 中噬中性白血球計數圖 74
圖 2-8、甘草甜素與甘草次酸對細菌脂多醣誘導肺炎之氣管滴注組
BALB/c 小鼠BALF 中噬中性白血球計數圖 75
圖 2-9、甘草甜素與甘草次酸對細菌脂多醣誘導肺炎之霧化吸入組
BALB/c 小鼠肺部病理切片圖 76
圖 2-10、甘草甜素與甘草次酸對細菌脂多醣誘導肺炎之氣管滴注組
BALB/c 小鼠肺部病理切片圖 77
圖 2-11、甘草甜素與甘草次酸對細菌脂多醣誘導肺炎之霧化吸入組
BALB/c 小鼠肺臟內抗氧化酵素活性之影響 78
圖 2-12、甘草甜素與甘草次酸對細菌脂多醣誘導肺炎之氣管滴注組
BALB/c 小鼠肺臟內抗氧化酵素活性之影響 79
圖 2-13、甘草甜素與甘草次酸對 RAW 264.7 細胞吞噬活性之影響
80
圖 2-14、甘草甜素對 RAW 264.7 細胞吞噬活性之影響 81
圖 2-15、甘草次酸對 RAW 264.7 細胞吞噬活性之影響 82
圖 3-1、甘草甜素與甘草次酸對順鉑誘導 BALB/c 小鼠腎毒性之動
物實驗設計 107
圖 3-2、甘草甜素對順鉑誘導之 BALB/c 小鼠血清 BUN、creatinine
與 LDH 表現之影響 108
圖 3-3、甘草次酸對順鉑誘導之 BALB/c 小鼠血清BUN、creatinine
與LDH表現之影響 109
圖 3-4、甘草甜素及甘草次酸對順鉑誘導之BALB/c小鼠腎臟型態變
化之影響 110
圖 3-5、甘草甜素及甘草次酸對順鉑誘導之 BALB/c 小鼠腎臟組織
病理變化之影響 111
圖 3-6、甘草甜素對順鉑誘導之BALB/c小鼠腎臟中抗氧化酵素
catalase、SOD、GPx、GRd、GST活性與GSH/GSSG比值
之影響 116
圖 3-7、甘草次酸對順鉑誘導之BALB/c小鼠腎臟中抗氧化酵素
catalase、SOD、GPx、GRd、GST活性與GSH/GSSG比值
之影響 118
圖 3-8、甘草甜素對順鉑誘導之BALB/c小鼠腎臟組織中丙二醛含
量之影響 120
圖 3-9、甘草次酸對順鉑誘導之BALB/c小鼠腎臟組織丙二醛含量
之影響 121
圖 3-10、甘草甜素及甘草次酸對順鉑誘導之 BALB/c 小鼠腎臟
NFκB 表現之影響 122
圖 3-11、甘草甜素及甘草次酸對順鉑誘導之 BALB/c 小鼠腎臟
TNF-α 表現之影響 124
圖 3-12、甘草甜素及甘草次酸對順鉑誘導之 BALB/c 小鼠腎臟
IL-1β 表現之影響 126
圖 3-13、甘草甜素及甘草次酸對順鉑誘導之 BALB/c 小鼠腎臟IL-6
表現之影響 128
圖 3-14、甘草甜素及甘草次酸對順鉑誘導之 BALB/c 小鼠腎臟
HMGB1 表現之影響 130
圖 3-15、甘草甜素及甘草次酸對順鉑誘導之 BALB/c 小鼠腎臟
Nrf2 表現之影響 132
圖 3-16、甘草甜素及甘草次酸對順鉑誘導之 BALB/c 小鼠腎臟
HO-1 表現之影響 134
圖 3-17、甘草甜素與甘草次酸緩解順鉑誘導腎毒性之可能機制圖 136
 
表次

表 1-1、生理環境下常見的活性物種 20
表 1-2、內生性與外生性的活性物種來源 20
表 2-1、霧化吸入組分組條件 54
表 2-2、氣管滴注組分組條件 55
表 3-1、動物實驗分組表 92
表 3-2、管餵甘草甜素對順鉑誘導之腎損傷模式之BALB/c小鼠組織
病理切片評估 112
表 3-3、管餵甘草次酸對順鉑誘導之腎損傷模式之 BALB/c小鼠組織
病理切片評估 113
表 3-4、管餵甘草甜素對順鉑誘導之腎損傷模式之BALB/c小鼠體重
之影響變化 114
表 3-5、管餵甘草次酸對順鉑誘導之腎損傷模式之BALB/c小鼠體
重之影響變化 115

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