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研究生:徐佑靈
研究生(外文):Yu-Ling Hsu
論文名稱:Peiminine在秀麗隱桿線蟲和SH-SY5Y細胞系的藥理和轉基因模型上的抗帕金森效力
論文名稱(外文):A study of the antiparkinsonian effect of peiminine using the pharmacological and transgenic models of Caenorhabditis elegans and SH-SY5Y cell
指導教授:傅如輝
指導教授(外文):Ru-Huei Fu
學位類別:碩士
校院名稱:中國醫藥大學
系所名稱:生物醫學研究所碩士班
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2021
畢業學年度:109
語文別:中文
論文頁數:93
中文關鍵詞:Peiminine帕金森病6-羥基多巴胺α-突觸核蛋白細胞凋亡自噬蛋白酶parkinARTSXIAP
外文關鍵詞:peiminine6-hydroxydopamineα-synucleinapoptosisproteasomeau-tophagyparkinARTSXIAP
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帕金森氏病(PD)是僅次於阿茲海默症第二常見的神經退行性疾病。目前真正的致病原因並不清楚,但與環境、遺傳因素及衰老有關。現在仍沒有成功的PD治療方法,治療策略基於PD的典型病理特徵,α-突觸核蛋白在細胞內的聚集以及中腦黑質中多巴胺能神經元的丟失為主要標的物。Peiminine(PMN)是平貝母(Fritillaria thunbergii)的主要成分,具有調節自噬和細胞凋亡,抑制神經炎症等效用。在這項研究中,我們使用秀麗隱桿線蟲(Caenorhabditis elegans)作為模型來評估PMN的神經保護潛力,以及在人SH-SY5Y細胞系中神經保護作用的可能機制。我們的研究發現,PMN治療暴露於6-羥基多巴胺(6-OHDA)的線蟲時,可以顯著改善食物感應行為並延長壽命,亦可以顯著減少多巴胺能神經元暴露於6-OHDA引起的損害。PMN還減少了轉基因線蟲株NL5901中α-突觸核蛋白的積累。此外,在SH-SY5Y細胞系中,PMN可以增加PINK1/parkin的表達,形成自噬的保護機制,從而增強泛素-蛋白酶體系統來介導PD的病理。並通過parkin途徑減少ARTS及誘導XIAP,藉此減少6-OHDA誘導及α-突觸核蛋白的積累所造成的細胞凋亡及損傷。在體內和體外實驗中,使用干擾RNA的方式來下調parkin表達可能會逆轉PD模型中PMN帶來的益處。PMN可能是PD治療的候選藥物,值得進一步研究。
Parkinson''s disease (PD) is the second most common neurodegenerative disease after Alzheimer''s disease. At present, the true cause of PD is unclear, but it is related to the environment, genetic factors and aging. There is still no successful treatment method for PD. The treatment strategy is based on the typical pathological features of PD, the accumulation of α-synuclein in cells and the loss of dopaminergic neurons in the substantia nigra of midbrain. Peiminine (PMN) is the main ingredient of Fritillaria thunbergia, which has the ability to regulate autophagy and apoptosis ,and inhibit neuroinflammation. Our research used Caenorhabditis elegans to evaluate the neuroprotective potential of PMN and the possible mechanism of this neuroprotective effect in the human SH-SY5Y cell line. This study found that PMN treatment with 6-hydroxydopamine (6-OHDA)-induced worm strains can significantly improve food-sensing behavior and prolong lifespan, and reduce the damage caused by exposure to 6-OHDA on dopaminergic neurons. PMN also reduced the accumulation of α-synuclein in transgenic worm strain NL5901. In addition, PMN can increase the expression of PINK1/parkin and form an autophagy protection mechanism, and enhancing the ubiquitin-proteasome system to mediate the pathology of PD. And through the parkin pathway, it can reduce ARTS and induce XIAP, thereby reducing cell apoptosis and damage caused by 6-OHDA and α-synuclein accumulation in SH-SY5Y cell line. In vivo and in vitro experiments, small interfering RNA to down-regulate parkin will reverse the benefits of PMN in our experimental PD models. PMN may be a drug candidate for PD treatment and is worthy of further study.
中文摘要 I
英文摘要 II
目錄 III
表附錄 VII
圖附錄 VIII
第一章 前言 1
第一節 研究背景 1
1.1.1介紹 1
1.1.2造成PD可能的機制 3
1.1.3 PD模型-秀麗隱桿線蟲與SH-SY5Y細胞系 7
1.1.4 PD模型中病理學標誌物 12
1.1.5 行為表型 14
1.1.6 中草藥目前在 PD 治療上的評估 18
1.1.7 Peiminine的簡介 21
第二節 研究目的 22
第二章研究方法 23
第一節 研究材料 23
2.1.1 秀麗隱桿線蟲的品系、維護及同步化 23
2.1.2 實驗用藥 23
2.1.3 線蟲生長培養皿(NGM) 23
2.1.4 LB培養皿 24
2.1.5 M9 緩衝液 25
2.1.6 S-medium 25
2.1.7 製備 OP50 菌液 26
第二節研究設計 27
2.2.1 食物清除率分析 27
2.2.2 6-OHDA誘導的DA神經元變性和PMN的處理 27
2.2.3多巴胺神經元的退行性的定量分析 27
2.2.4 食品敏感性行為分析 27
2.2.5 壽命分析 28
2.2.6 α-突觸核蛋白聚集的定量分析 28
2.2.7 活性氧的測定 28
2.2.8 秀麗隱桿線蟲的蛋白質表達定量分析 29
2.2.9 秀麗隱桿線蟲的RNA萃取和qPCR分析 29
2.2.10秀麗隱桿線蟲的蛋白酶體活性分析 29
2.2.11秀麗隱桿線蟲的自噬活性分析 30
2.2.12 秀麗隱桿線蟲的pdr-1 RNA干擾(RNAi)分析 30
2.2.13 SH-SYSY細胞系的培養及6-OHDA的處理 30
2.2.14瞬時過表達α-突觸核蛋白的SH-SY5Y細胞系的產生 30
2.2.15 SH-SY5Y 細胞免疫螢光染色 31
2.2.16 SH-SY5Y 細胞活性測試 31
2.2.17 SH-SY5Y細胞系的蛋白質印跡分析 31
2.2.18 SH-SY5Y細胞系中的parkin小RNA干擾 32
2.2.19 SH-SY5Y細胞系粒線體膜電位的測定 32
2.2.20 SH-SY5Y 細胞系中 Hoechst 33258 的核染色 32
2.2.21 流式細胞儀檢測細胞凋亡 32
2.2.22 SH-SY5Y細胞株中蛋白酶體活性的測定 33
2.2.23 SH-SY5Y細胞株中的酸性囊狀胞器的染色 33
2.2.24 SH-SY5Y細胞株中的自噬活性測定 33
2.2.25統計分析 33
第三章研究結果 35
3.1 利用食物清除率測試分析Peiminine處理線蟲的最適濃度 35
3.2 Peiminine預處理減少了 6-OHDA 暴露線蟲的多巴胺能 (DA) 神經元退化 35
3.3 Peiminine處理恢復了暴露在6-OHDA的N2線蟲的食物敏感性行為缺陷 35
3.4 Peiminine處理可延長暴露6-OHDA的N2線蟲的壽命 36
3.5 Peiminine處理可減少轉基因蟲株NL5901的肌肉細胞中人類α-突觸核蛋白 (α-Syn)的積累 36
3.6 Peiminine可減少6-OHDA暴露的線蟲模型中的活性氧水平及增強Pink1和Pdr-1的表達 36
3.7 Peiminine預處理可增強 NL5901 線蟲內蛋白酶體活性和自噬及Pdr-1的表達 37
3.8利用RNAi抑制Pdr-1的表達可以消除Peiminine逆轉線蟲中6-OHDA誘導的DA神經元變性的能力。 37
3.9 PMN 處理可減少 6-OHDA 與 α-Syn 過表達對 SH-SY5Y 細胞的毒性 38
3.10 Peiminine減少SH-SY5Y細胞暴露在6-OHDA引起的細胞凋亡 38
3.11 Parkin siRNA逆轉Peiminine介導暴露在6-OHDA的SH-SY5Y細胞中的抗凋亡能力 39
3.12 Peiminine增加α-突觸核蛋白(α-Syn)過表達的SH-SY5Y細胞的蛋白酶體活性與自噬,RNAi抑制 parkin 的表現消除了PMN增強泛素-蛋白酶體系統(UPS)活性和自噬的效力 39
3.13 PMN可能藉由 parkin 調節下游ARTS和XIAP活性而達到其抗巴金森的效力 40
第四章討論 41
第五章結論 46
表附錄 69
圖附錄 71
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