靈芝 (Ganoderma lucidum) 作為中國藥用食材已有上千年歷史，本研究室已建立固態發酵靈芝培養菌絲體之最適培養基及培養條件。本研究沿用此條件探討發酵槽通氣量 (0, 0.2, 0.5 vvm) 對靈芝固態發酵產物及 γ-胺基丁酸 (GABA) 產量之影響。進一步以人類神經母瘤 SH-SY5Y 細胞誘發氧化損傷模式探討，固態發酵靈芝菌絲體萃取物產物對神經細胞氧化傷害的保護效果。靈芝固態發酵後產物蛋白質 (21.37 ± 0.01%) 與脂質 (4.38 ± 0%)，明顯高於未發酵培養基之蛋白質 (11.58 ± 0.01%) 與脂質 (2.97 ± 0%) 含量。靈芝固態發酵產物含有 30.17 ± 1.38% 葡聚醣、43.36 ± 2.19 mg/g 三萜及 568.61± 14.2 mg/g GABA。在 0.2 vvm 通氣量可增加產物三萜含量 (37.51 ± 0.69 mg/g)，但通氣量高低對產物的葡聚醣無顯著影響。固態靈芝菌絲體產物以 10% 酒精萃取 (萃取物A)、70oC 水萃 (萃取物B) 及熱水萃取再經由酒精沉澱 (萃取物C) 萃取之三種萃取物以萃取物 C 所含葡聚醣最高，萃取物 A 與 B 所含 GABA 最高。以 100 μM H2O2 誘導 SH-SY5Y 神經細胞損傷之模式觀察發現，SH-SY5Y 細胞先以 0.26 μg/mL 三種萃取物預處理，靈芝萃取物 A、B、C 可使神經細胞存活率分別較控制增加 37.5%、48.9% 及 3.96%。細胞先以 H2O2 誘導氧化損傷後，再給予 0.26 μg/mL 靈芝萃取物 A、B、C，可使神經細胞存活率分別增加 38.6%、47.0% 及 7.9%。顯示靈芝發酵產物對神經細胞氧化傷害具保護與修護效果，其活性成分主要來自發酵產物所含 GABA 顯著增加 SH-SY5Y 細胞超氧歧化酶活性來降低 H2O2 對細胞造成的傷害。

Ganoderma lucidum has been used for over 2000 years in traditional Chinese medicine. The culture medium and condition for the solid-state cultivation of G. lucidum mycelia had been established previously. One of the aims of this study was to investigate the effect of ventilation on the production of the bioactive substances of glucan, triterpene and γ-aminobutyric acid (GABA) by G. lucidum using a novel solid-state fermenter. After 28 days of cultivation, the protein content of G. lucidum fermented product is elevated form 11.58 ± 0.01% to 21.37 ± 0.01%; the lipid content is elevated from 2.97 ± 0% to 4.38 ± 0%. The G. lucidium fermented product was extracted by 10% ethanol (extract A), 70oC warm water (extract B) and hot water following alcohol precipitation (extract C). All extracts contained the three bioactive substances of glucan, triterpene and GABA, with the extract A and extract B being the highest GABA content and the extract C the highest glucan content. The protective effects of the 3 extracts of G. lucidum fermented products on H2O2 (100 μM)–damaged neuroblastoma SH-SY5Y cells were further evaluated. Pretreatment of cells with the extracts of A and B at 0.26 μg/mL, followed by H2O2 damage, significantly increased cell viability by 37.5% and, 48.9%, respectively; while the extract C did not significantly increase cell viability. In addition, after being damaged by H2O2 and followed by the treatment with the extract A and B, the cell viability was significantly increased by 38.6% and 47.0%, respectively; while the extract C did not significantly increase cell viability. A significant increase in superoxide dismutase (SOD) activity was observed in the extract B treated group and GABA standard. These results suggested that GABA component in G. lucidum fermented product is the major contributor for protection of SH-SY5Y cells from oxidative damage. In conclusion, this study revealed that the G. lucidum fermented GABA-rich product has potential to prevent neuronal oxidative damage as well as to facilitate neuronal recovery.

壹、前言 1
貳、文獻整理 3
一、失智症與阿茲海默症 3
二、阿茲海默症 3
1.阿茲海默症成因 3
2.環境氧化壓力與阿茲海默症的關係 4
3.細胞內生性抗氧化酵素系統 5
4.模擬阿茲海默症之體外模式 6
5. β-amyloid peptide (Aβ) 6
三、SH-SY5Y細胞株 7
1. SH-SY5Y之特性 7
2. 臨床上研究意義 7
四、γ-胺基丁酸 8
4.1 γ-胺基丁酸之結構 8
4.2 γ - 胺基丁酸的生成途徑 8
4.3.γ-胺基丁酸的接受器 9
4.4.γ-胺基丁酸在人體之合成、降解與釋放 10
4.5 γ-胺基丁酸的生理活性 11
五、靈芝 12
1.簡介 12
2.栽培方式 12
2.1傳統培養方式及最適生長條件 13
2.2子實體培養方式 14
2.3 菌絲體培養方式 14
3.靈芝子實體之生理調節機能 15
3.1.靈芝之活性成分 16
六、靈芝應用於神經退化疾病的研究 18
參、實驗設計 20
肆、實驗材料與方法 21
一、實驗材料 21
二、儀器設備 23
三、實驗方法 25
1.固態發酵之靈芝菌株活化及發酵條件 25
1.1靈芝菌株保存與活化 25
1.2靈芝接種液之製備 25
1.4 固態發酵槽培養 26
1.5 通氣量對靈芝固態發酵槽培養活性物質之影響 26
2. 靈芝固態發酵品之一般成分分析 26
2.1水分測定 26
2.2灰分測定 27
2.3 粗脂肪測定 27
2.4 粗蛋白測定 27
2.5碳水化合物含量 28
3.靈芝萃取物的製備 28
3.1靈芝粗多醣之萃取 28
3.2靈芝粗三萜之萃取 28
3.3靈芝粗 GABA 之萃取 28
4.靈芝發酵品及靈芝萃取物之分析 29
4.1靈芝發酵品及靈芝萃取物之 GABA 含量分析 29
4.2靈芝發酵品及靈芝萃取物之 β - 葡聚糖含量分析 29
4.2.1測定總葡萄糖分析方法 30
4.3.2測定 α-聚葡萄糖之分析方法 30
4.4總三萜含量 31
5.靈芝固態發酵萃取物對 SH-SY5Y 細胞存活率之影響 32
5.1 SH-SY5Y細胞培養方式 32
5.2靈芝固態發酵萃取物對 SH-SY5Y 細胞存活率之影響 32
6.靈芝固態發酵萃取物保護神經細胞對抗氧化壓力之探討 32
6.1建立以H2O2誘導SH-SY5Y細胞氧化壓力之實驗模式 32
6.2靈芝固態發酵萃取物保護 SH-SY5Y 細胞對抗 H2O2 之氧化壓力 33
6.3靈芝固態發酵萃取物修護 SH-SY5Y 細胞對抗 H2O2 氧化壓力 33
7.靈芝固態發酵萃取物對 SH-SY5Y細胞胞內酵素活性之影響 33
7.1建立 SH-SY5Y 細胞在氧化壓力誘導下之胞內酵素分析模式 33
7.2靈芝固態發酵萃取物保護 SH-SY5Y 細胞對抗 H2O2 之氧化壓力之胞內酵素活性分析 33
7.3靈芝固態發酵萃取物修復 SH-SY5Y 細胞對抗 H2O2 之氧化壓力之胞內酵素活性分析 34
8.細胞分析 34
8.1 細胞存活率分析 34
8.2細胞蛋白質萃取及定量 35
8.3 細胞內抗氧化酵素活性測定 35
9.統計分析 37
伍、實驗結果與討論 38
一、靈芝穀物發酵前後一般成份組成 38
二、靈芝菌絲體固態發酵培養對其活性物質葡聚醣、三萜含量及 GABA 含量之影響 39
三、固態發酵槽通氣量對靈芝菌絲體發酵產物其葡聚糖及總三萜含量之影響 39
四、靈芝固態發酵萃取物之活性物質葡聚醣、三萜含量及 GABA 含量分析 40
五、氧化壓力模擬 SH-SY5Y 神經損傷之細胞存活率之影響 41
六、各萃取物對細胞氧化壓力之保護及修護效果探討 41
七、靈芝固態發酵萃取物 B 對 SH-SY5Y 細胞內抗氧化酵素活性之影響 44
陸、 結論 48
柒、參考文獻 49
捌、圖表 65
圖表目錄
表一、靈芝穀物固態發酵前後一般成份分析 65
表二、固態培養基於靈芝菌絲體培養前後葡聚醣三萜及 γ - 胺基丁酸含量 66
表三、固態發酵槽通氣量對靈芝菌絲體培養物活性物質葡聚糖及總三萜含量之影響 67
表四、靈芝固態發酵萃取物之葡聚醣、三萜及 GABA 含量 68
圖ㄧ、GABA 標準品 (A) 與靈芝 A 菌 發酵產物中 (B) GABA 含量之 HPLC 分析圖譜 69
圖二、固態發酵槽培養 7 天，不同通氣量其 GABA含量之 HPLC 分析圖譜 70
圖三、不同萃取物之 GABA 含量之 HPLC 分析圖譜 (A) 靈芝萃取物 A (B) 靈芝萃取物B (C) 靈芝萃取物C 71
圖四、GABA標準品之HPLC 檢量線 72
圖五、SH-SY5Y 細胞經雙氧水處理 24小時之存活率 73
圖六、靈芝發酵萃取物 A對過氧化氫誘導SH-SY5Y細胞毒性之保護及修護作用 74
圖七、靈芝發酵萃取物 B對過氧化氫誘導SH-SY5Y細胞毒性之保護及修護作用 75
圖八、靈芝發酵萃取物 C對過氧化氫誘導SH-SY5Y細胞毒性之保護及修護作用 76
圖九、GABA標準品對過氧化氫誘導SH-SY5Y細胞毒性之保護及修護作用 77
圖十、以過氧化氫誘發SH-SY5Y細胞氧化傷害，靈芝萃取物 B對超氧歧化酶活性之保護及修護作用 78
圖十一、以過氧化氫誘發SH-SY5Y細胞氧化傷害，靈芝萃取物 B對觸酶活性之保護及修護作用 79
圖十二、以過氧化氫誘發SH-SY5Y細胞氧化傷害，靈芝萃取物 B對麩胱甘肽過氧化酶活性之保護及修護作用 80

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