臺灣博碩士論文加值系統

黃金銀耳菌(Tremella mesenterica Retz.: Fr.,)為一類酵母真菌(yeast-like fungus)，具有免疫刺激、抗輻射效應、降血糖、抗發炎、降膽固醇、抗過敏及保肝等生物活性，活性主要成分來自於多醣體。菌體生理狀態與細胞形態息息相關，應用光學顯微鏡結合影像處理技術的影像分析方法是可做為菌體形態監控的工具。浸液發酵培養具有生長一致、菌齡整齊、週期短、產量高、成本低及產物易提取精製等優點。發酵產程中培養基及培養環境會影響菌體的形態及生理狀態，進而影響發酵產物的產量、組成及生物活性。藥用真菌或其所產生多醣體或醣蛋白具有刺激非專一性免疫系統、活化免疫細胞、促進細胞激素分泌，經由刺激宿主的防禦機制而發揮抗腫瘤活性的能力。因此，本研究主要目的為探討不同浸液培養條件對黃金銀耳菌形態特性、多醣體生成及其生物活性之影響。
本論文分三部分: (一) 以影像分析方法對不同培養條件下的細胞形態特徵做具體的描述，並進一步分析形態特徵與生質量及胞外多醣體生成之關係； (二) 以不同碳源培養黃金銀耳菌生產胞外多醣體是否影響細胞激素刺激之效應；及 (三) 比較黃金銀耳浸液培養發酵產物之胞外多醣體(EPS)、胞內多醣體(IPS)及酒精萃出物(EE)對人類肺癌細胞株A549誘發細胞凋亡之效應。
結果顯示 (1) 液態培養黃金銀耳類酵母菌的形態受培養條件包括pH、溫度、氮源及碳氮比等因子所影響，然而並未發現上述等形態特徵與黃金銀耳菌生質量或其胞外多醣生成量的相關性。但在發酵產程中，發現伸長度小於2.5 m的比率約大於90%以上即表示達到最高的生質量；而伸長度小於2.5 m的比率低於80%以下，可發現胞外多醣體已達到最高值(2.38 g/L)。此外，觀察出芽率的變化曲線發現，出芽率的轉折點即為生質量的最高點（7.02 g/L），而後再出現第二個轉折點時即表示胞外多醣已達最高值。此結果顯示黃金銀耳菌形態特徵中伸長度及出芽率的變化與其生質量及胞外多醣體的產率具有相關性，可將伸長度及出芽率的變化作為監控生產黃金銀耳菌發酵產程的參考指標之一。
(2) 以不同碳源培養黃金銀耳菌生產胞外多醣體之結果，顯示培養基中以葡萄糖、甘露糖為碳源及與半合成培養基相較之下所得之生質量以葡萄糖(7.42 g/L)及半合成培養基(7.5 g/L)為最高，多醣體則以半合成培養基(7.68 g/L)為最高。在四種培養基中所得之多醣體，其單醣組成中是由甘露糖、木糖、半乳糖及葡萄糖以不同比例所組成，葡萄糖醛酸含量亦有差異。此外，以木糖及葡萄糖為碳源所得之胞外多醣體可明顯刺激巨噬細胞分泌較多的TNF-、IL-6及NO。由於木糖及葡萄糖為碳源所生產之胞外多醣體之單醣組成中甘露糖比例較高，甘露糖可藉與巨噬細胞表面的受器結合來提高其免疫活性，培養基中木糖及葡萄糖為碳源時生產之黃金銀耳菌胞外多醣體有利於提高其免疫調節活性。
(3) 黃金銀耳浸液培養發酵產物之酒精萃出物(EE)可完全抑制肺癌細胞株A549之生長，而胞外多醣體(EPS)及胞內多醣體(IPS)並無此活性。以流式細胞儀分析細胞凋亡率結果發現，EE可誘導細胞凋亡，與對照組相較之下可達到32.8%的凋亡率。EE處理組可造成粒線體膜電位的變化、活性氧生成及凋亡蛋白酶-3(caspase-3)的活化，顯示EE可藉由粒線體路徑誘導A549細胞凋亡來降低肺癌細胞株A549的存活率。

Tremella mesenterica Retz.: Fr., belongs to the so-called ‘Jelly Mushrooms’group, has pharmacological activities, including cytokine-stimulating, anti-diabetic, anti- inflammatory, vascular-stimulating, hypocholesterolemic, anti-allergic and hepatoprotective effects. Submerged fermentation has the potential for higher mycelial production in a compact space, stable product composition under controlled environments and in shorter time with fewer chances for contamination. Culture medium and process is important for the yield of cultivation products, culture metabolic activity and its bioactivity. Therefore, the optimization of medium including both carbon source and nitrogen source might improve the production of various substances of nutraceutical, pharmaceutical and functional foods. Cell morphology is strongly related to culture metabolic activity, the application of image analysis has been suggested as a monitoring tool. Some polysaccharides or polysaccharide–protein complexes from mushrooms are able to stimulate the non-specific immune system, to activate effector cells to secrete cytokines and to exert antitumor activity through the stimulation of the host's defence mechanism. Therefore, the objectives of this study were to investigate the effect of culture conditions on the changes in cell morphology, the polysaccharide production rate, and the bioactivities of Tremella mesenterica.
There are three parts included in this study: (1) The effect of different culture conditions on morphological characterization of T. mesenterica and the relationship between polysaccharide production rate and cell morphology bry image analysis; (2) Effects on cytokine-stimulating activities of extracellular polysaccharides (EPS) from T. mesenterica with various carbon sources; and (3) Induction of apoptosis in human lung carcinoma A549 epithelial cells with an ethanol extract of T mesenterica.
Results show that (1) the morphological characterization (including cell roundness, elongation, area and budding ratio) changes of T. mesenterica cells depend on the culture conditions such as pH, temperature, nitrogen sources and C/N ratio. There appeared to be no causal relationship between those morphological characterizations and polysaccharides production rate. The morphological form of T. mesenterica cells also change during cultivated in batch fermentation experiments. However, the changes in biomass or EPS production rate of T. mesenterica have been found to correlate with the changes in ratio of elongation or budding cells in the culture. In batch cultures it was therefore possible to control fermentation process by monitoring the changes in ratio of elongation or budding cells in the culture; (2) the predominant sugars in EPS identified in this study were glucose, mannose, xylose, and galactose. The component sugar and uronic acids within the EPS vary with the different carbon sources, a variation which also affects cytokine (interlukin-6 and tumor necrosis factor-α) and nitric oxide production in RAW 264.7 macrophage cells. Xylose and glucose were better carbon sources from the viewpoint of immunomodulatory activity due to the relatively high mannose content in EPS; (3) The EE (ethanol extract) of T. mesenterica, but not the EPS or the IPS (intracellular polysaccharides), almost completely inhibited the growth of A549 cells. The results of Annexin V-FITC/PI staining and flow cytometric analysis indicated that the percentage of Annexin V+/PI- cells in EE-treated cells increased to 32.8%. The results of further investigation showed a disruption of mitochondrial transmembrane potential, the production of reactive oxygen species (ROS), and the activation of caspase-3 protein in EE-treated cells. These findings indicate that EE can decrease cell viability and induce apoptosis in A549 cell lines by activating a mitochondrial pathway. Taken together, these results suggest that intake of EPS or EE from T. mesenterica could contribute to the antitumor effect occur by activating immune responses in the host and/or inducing apoptosis in cancer cell.

目錄

封面內頁
簽名頁
授權書 iii
中文摘要 iv
英文摘要 vii
誌謝 ix
目錄 xi
圖目錄 xviii
表目錄 xxii

1. 緒言 1
2. 文獻回顧 4
2.1 黃金銀耳菌簡介 4
2.2 黃金銀耳菌深層培養 6
2.3 黃金銀耳多醣體 7
2.3.1 菇類多醣體之化學特性 7
2.3.2 黃金銀耳多醣體之化學特性 10
2.4 黃金銀耳菌之生理活性 11
2.4.1 抗腫瘤活性(Antitumor activity) 11
2.4.2 免疫調節(Immunomodulation) 14
2.4.3 降膽固醇(Hypocholesterolemic activity) 16
2.4.4 降血糖(Antidiabetic activity) 16
2.4.5 抗輻射效應(Antiradiation effects) 18
2.4.6 抗發炎(Anti-inflammation) 19
2.4.7 抗過敏活性(Antiallergic action) 20
2.5 影像分析(Image analysis) 20
2.6 影響發酵產物之因素 23
2.6.1 培養溫度(Temperature) 23
2.6.2 pH值24
2.6.3 生物反應器的種類(Bioreactor’s type) 25
2.6.4 氮源(Nitrogen source) 25
2.6.5 碳源(Carbon source) 27
2.6.6 碳/氮比(C/N ratio) 27
2.7 免疫反應 28
2.7.1 巨噬細胞 29
2.7.2 脂多醣體 30
2.7.3 細胞激素 31
2.7.3.1 腫瘤壞死因子(TNF) 31
2.7.3.2 介白質6號(IL-6) 33
2.7.3.3 一氧化氮(NO) 33
2.8 細胞凋亡 34
2.8.1 細胞凋亡路徑 37
2.8.2 粒線體與細胞凋亡 38
2.8.3 活性氧與細胞凋亡 40
2.8.4 凋亡蛋白酶(Caspases) 40
3. 黃金銀耳菌發酵產程中類酵母菌細胞形態特性與其多醣體生成關係之探討 45
3.1 前言 46
3.2 材料與方法 47
3.2.1 試驗菌株 47
3.2.2 菌種保存與維持 48
3.2.3 種菌製備 48
3.2.4 基礎培養基組成 48
3.2.5 不同溫度培養試驗 48
3.2.6 不同pH值培養試驗 49
3.2.7 不同碳氮比培養試驗 49
3.2.8 不同氮源培養試驗 49
3.2.9 發酵槽培養 50
3.2.10分析方法 50
3.2.10.1 pH值測定 50
3.2.10.2生質量(Biomass)測定 50
3.2.10.3發酵液殘糖分析 50
3.2.10.4胞外多醣體含量測定 51
3.2.11影像分析 51
3.2.11.1玻片製備 51
3.2.11.2影像擷取與分析 51
3.2.12統計分析 52
3.3 結果與討論 52
3.3.1 培養溫度對黃金銀耳菌生質量、胞外多醣體產量及形態之影響 52
3.3.2 培養基起始pH值對黃金銀耳菌生質量、胞外多醣體產量及形態之影響 54
3.3.3 培養基中不同氮源黃金銀耳菌生質量、胞外多醣體產量及形態之影響 55
3.3.4 培養基中碳氮比對黃金銀耳菌生質量、胞外多醣體產量及形態之影響 56
3.3.5 發酵產程中黃金銀耳菌生質量、胞外多醣體及菌體形態參數之變化 57
4. 培養基碳源種類對黃金銀耳多醣體產量、化學特性及細胞激素之影響 76
4.1 前言 77
4.2 材料與方法 79
4.2.1 試驗菌株 79
4.2.2 不同碳源種類培養 79
4.2.3 類酵母菌菌體生質量及胞外多醣體的定量 79
4.2.4 發酵液殘糖分析 80
4.2.5 中性單醣組成之測定 80
4.2.6 葡萄糖醛酸分析 80
4.2.7 一般成分分析 81
4.2.7.1 蛋白質測定 81
4.2.7.2 脂質測定 82
4.2.7.3 水分含量測定 82
4.2.7.4 灰分測定 83
4.2.7.5 粗纖維含量測定 83
4.2.7.6 碳水化合物含量測定 84
4.2.8 細胞培養 84
4.2.8.1 細胞活化及培養 84
4.2.8.2 繼代方法 84
4.2.8.3 培養基的組成 85
4.2.8.4 樣品製備 85
4.2.8.5 試驗細胞培養 85
4.2.8.6 NO檢測 86
4.2.8.7 細胞激素分泌之測定 86
4.2.9 統計分析 86
4.3 結果 86
4.3.1 不同培養時間對菌體生質、胞外多醣體及胞內多醣體產量之影響 86
4.3.2培養基碳源對菌體生質量及胞外多醣體產量之影響 87
4.3.3不同碳源培養基所得菌體細胞與胞外多醣體的化學特性 88
4.3.4 類酵母菌細胞一般成分分析 89
4.3.5不同碳源所得多醣體對巨噬細胞分泌之TNF-α及IL-6之影響 91
4.3.6不同碳源培養產生之多醣體對巨噬細胞分泌一氧化氮(NO)之影響 91
4.4 討論 92
5. 黃金銀耳類酵母菌浸液培養菌體之酒精萃取物誘導肺癌細胞株A549細胞凋亡機制之探討 102
5.1 前言 103
5.2 材料與方法 105
5.2.1 試驗菌株 105
5.2.2 發酵槽培養 105
5.2.3 胞外多醣體(EPS)、胞內多醣體(IPS)及黃金銀耳菌酒精抽出物(EE)樣品之製備105
5.2.4 細胞存活率測定 106
5.2.5 以人類周邊單核球(Perpheral blood mononuclear cells，PBMC) 檢測EE對正常細胞之毒性效應 107
5.2.6 以Annexin V-FITC/PI雙染試驗檢測細胞凋亡率 108
5.2.7以Flow cytometry 檢測細胞內活性氧的生成 109
5.2.8以Flow cytometry 檢測早期粒線體膜電位的變化 110
5.2.9西方轉漬法(Western blot)分析凋亡蛋白酶-3的表現 110
5.2.9.1 細胞收集及蛋白質測定 110
5.2.9.2聚丙烯醯胺膠電泳(SDS-PAGE electrophoresis assay) 111
5.2.9.3 西方轉漬法(Western blot assay) 111
5.2.10 形態觀察 112
5.2.11 統計分析 113
5.3 結果 113
5.3.1 細胞存活率試驗 113
5.3.2 EPS、IPS及EE誘導A549細胞凋亡之效應 114
5.3.3 EE對A549細胞形態之影響 114
5.3.4 EE對粒線體膜電位的影響 114
5.3.5 EE對活性氧生成之影響 115
5.3.6 EE對A549細胞株凋亡蛋白酶-3表現之影響 115
5.4討論 115
6. 結論 127
參考文獻 128
附錄 160

圖目錄

圖2.1 A：銀耳銀耳的酸性葡萄糖醛酸木糖聚甘露多醣體的結構；B：黃金銀耳B：黃金銀耳的酸性葡萄糖醛酸木糖聚甘露多醣體結構 43
圖2.2 哺乳動物的細胞死亡路徑模式 44
圖3.1 應用Simple PCI軟體處理黃金銀耳菌體之流程 61
圖3.2 浸液發酵培養中黃金銀耳菌於各形態參數定義下菌體形態之分類 62
圖3.3 不同培養溫度(20、25及30C)對黃金銀耳菌培養後生質量及胞外多醣體產量之影響 63
圖3.4 黃金銀耳菌於不同培養溫度下浸液之菌體形態(1000X) (A) 20C (B) 25C (C) 30C 64
圖3.5 黃金銀耳菌於不同培養溫度下各項菌體形態參數(圓度小於0.8，伸長度小於2.5 m，面積大於8 m2及出芽率)所佔之比率 65
圖3.6 基礎浸液培養基中以不同起始pH值對黃金銀耳菌生質量及胞外多醣體產量之影響 66
圖3.7 浸液培養基中，不同培養基起始pH值(A: 3.5; B: 4.5; C: 5.5; D: 6.5; E: 7.5)培養之黃金銀耳菌菌體形態(1000X) 67
圖3.8 浸液培養基中不同起始pH值對黃金銀耳菌各種菌體形態參數(圓度小於0.8，伸長度小於2.5 m，面積大於8 m2及出芽率)所佔比例之影響 68
圖3.9 浸液培養基中以不同氮源培養對黃金銀耳菌生質量及胞外多醣體產量之影響69
圖3.10 浸液培養基中以不同氮源培養黃金銀耳菌之菌體形態(A)L-麩醯胺酸；(B)酪蛋白；(C)離胺酸；(D)丙胺酸(E)硫酸銨 70
圖3.11 浸液培養基中以不同氮源培養對黃金銀耳菌菌體形態參數(圓度小於0.8，伸長度小於2.5 m，面積大於8 m2及出芽率)所佔比例之影響 71
圖3.12 浸液培養基中以不同之碳氮比培養對黃金銀耳菌生質量及胞外多醣體產量之影響 72
圖3.13 浸液培養基中不同碳氮比培養之黃金銀耳菌菌體形態(1000X) (A) 1:5 (B) 1:1 (C) 5:1 (D) 12:1 (E) 24:1 (F) 36:1 73
圖3.14 浸液培養基中以不同碳氮比培養對黃金銀耳菌各種菌體形態參數(圓度小於0.8，伸長度小於2.5 m，面積大於8 m2及出芽率)所佔比例之影響 74
圖3.15 (A)黃金銀耳菌於五公升發酵槽培養期間醱酵液中生質量、胞外多醣體產量之變化。(B-E)為培養期間黃金銀耳菌各項菌體形態參數所佔之比例 75
圖4.1 黃金銀耳菌(Tremella mesenterica)於五公升基礎培養基醱酵槽培養期間菌絲體胞外多醣體、胞內多醣體、生質量、發酵液pH值及殘糖含量之變化 95
圖4.2 浸液培養基中不同碳源(葡萄糖、甘露糖及木糖)及半合培養基培養對黃金銀耳菌生質量及胞外多醣體產量之影響 96
圖4.3 浸液培養基中不同碳源(葡萄糖、甘露糖及木糖)及半合成培養基培養對黃金銀耳菌生產之胞外多醣體中葡萄糖醛酸含量之影響98
圖5.1 以木糖為碳源浸液培養黃金銀耳菌生產之胞外多醣體、胞內多醣體及菌體酒精萃取物之製備流程 118
圖5.2 A549細胞存活率檢測 119
圖5.3 以MTT方法檢測EE對細胞存活率之影響 120
圖5.4 以Trypan blue染色方法檢測EE對人類周邊單核球細胞(PBMC)存活率之影響 121
圖5.5 以流式細胞儀檢測EE處理組的細胞凋亡率 122
圖5.6 以位相差顯微鏡(200X)分別於(A)0 (對照組)(B) 12 (C) 24 (D) 32 (E) 40及(F) 46小時觀察經EE處理對A549細胞株形態之影響 123
圖5.7 EE處理A549細胞株之粒線體膜電位變化 124
圖5.8 EE處理A549細胞株活性氧生成之變化 125
圖5.9 以0.5 mg/ml EE處理之A549細胞於特定時間以西方點墨法檢測之凋亡蛋白酶-3活性，並以β-actin為內標 126


表目錄

表4.1 浸液培養基中不同碳源(葡萄糖、甘露糖及木糖)及半化合培養基培養對黃金銀耳菌生產之胞外多醣體中單醣組成含量之影響 97
表4.2 浸液培養基中不同碳源(葡萄糖、甘露糖及木糖)及半化合培養基培養對黃金銀耳菌生產之胞外多醣體中單醣組成含量之影響 99
表4.3 浸液培養基中不同碳源培養發酵生產所得胞外多醣體對Raw264.7巨噬細胞株細胞激素TNF-α及IL-6之影響 100
表4.4 浸液培養基中不同碳源培養黃金銀耳菌發酵生產所得胞外多醣體對Raw264.7巨噬細胞株一氧化氮產出之影響 101

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