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研究生:盧俐羽
研究生(外文):Li-Yu Lu
論文名稱:石蓮花對缺血壓力下血腦障壁保護機制的探討:β-catenin的參與
論文名稱(外文):Molecular mechanism responsible for Graptopetalum paraguayense-mediated BBB protection against cerebral ischemia : β-catenin involvement
指導教授:葛其梅葛其梅引用關係
口試委員:陳春榮王瑱瑄
口試日期:2020-01-21
學位類別:碩士
校院名稱:國立中興大學
系所名稱:生命科學系所
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2020
畢業學年度:108
語文別:中文
論文頁數:60
中文關鍵詞:血腦障壁石蓮花水萃物沒食子酸β-catenin缺血性中風
外文關鍵詞:Blood-brain barrierGraptopetalum paraguayenseGallic acidβ-cateninIschemic stroke
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缺血性中風是一種神經退化疾病,除腦細胞明顯受損之外,亦會造成血腦障壁 (Blood-brain barrier;BBB)的破壞造成通透性的提升,加劇缺血腦組織之發炎受損程度。近年來實驗室在動物及細胞實驗中均證實石蓮花水萃物(Water extract of Graptopetalum paraguayense;WGP)對缺血大鼠腦組織及不同腦細胞均有保護效益。但WGP對缺血壓力下受損的BBB是否具有保護效益,及參與其中的保護機轉尚有待釐清。已知β-catenin除了是血管內皮細胞壁處重要結構蛋白外,若入核亦可做為副轉錄因子和T細胞轉錄因子(TCF)結合調控基因表現。本論文因此首次評估WGP及其主成分沒食子酸(Gallic acid;GA)是否透過 β-catenin保護缺血壓力下BBB的細胞結構及屏障性。本論文的研究重點有三項1)評估體外缺血(glucose-oxygen-serum deprivation;GOSD)對BBB細胞成員之存活及BBB模組通透性之傷害;2)評估WGP或GA是否具有保護GOSD環境下BBB結構及功能之功效;3)釐清WGP或GA是否可透過提升β-catenin,來保護GOSD環境下星芒狀細胞和內皮細胞之存活,並調控細胞中血管調控因子(Ang-1或VEGF)之蛋白表現,進而保護BBB之屏障性。實驗中主要利用體外缺血模式(GOSD),大腦內皮細胞/第四型膠原蛋白/星芒狀細胞組成之體外BBB細胞模組做為研究平台,並使用化學抑制劑DAQZ (β-catenin抑制劑)來評估β-catenin是否參與WGP或GA對BBB之調控。使用分析方法包括台盼藍染色、細胞免疫螢光染色、西方墨點法、細胞貼附分析等方法。研究結果顯示GOSD處理明顯提升體外BBB細胞模組之通透性,但抑制星芒狀細胞與大腦內皮細胞的存活和β-catenin的總蛋白含量,同時亦促使β-catenin自細胞膜內往核內移動,顯示GOSD可能利用β-catenin入核去調控星芒狀細胞和內皮細胞的基因表現。低劑量之WGP及GA(0.1μM)均可透過提升β-catenin蛋白量來抑制被GOSD提升的BBB通透性,亦可有效提升GOSD壓力下星芒狀細胞及大腦內皮的存活,及星芒狀細胞和內皮細胞的貼附性。因WGP或GA增加的β-catenin可以磷酸化(活化)ERK1/2或AKT來保護GOSD星芒狀細胞及大腦內皮細胞之存活。WGP亦可透過β-catenin提升大腦內皮細胞中Ang-1但抑制VEGF之蛋白表現,而GA則可透過β-catenin提升星芒狀細胞中Ang-1之蛋白表現,共同提升BBB屏障功能。另外WGP亦可抑制GOSD星芒狀細胞中VEGF之表現來保護BBB但不經β-catenin的媒介。整體而言本研究首次證實WGP及GA具有保護BBB的功效;WGP和GA可以透過對β-catenin蛋白量的提升,保護BBB細胞成員的存活(經由活化ERK及AKT),及血管壁之穩定性(Ang-1表現之提升、VEGF表現之下降)。另外WGP及GA亦可促進星芒狀細胞及內皮細胞的貼附作用,但是否和 β-catenin有關尚有待釐清。經由上述研究成果更進一步提升我們對WGP抗中風機轉的了解,及未來WGP在治療腦中風之臨床價值。
Cerebral ischemia is a neurodegenerative disease, it causes not only brain cell injury but also destruction of the blood-brain barrier(BBB), which further increased the BBB permeability and brain inflammation. Recent studies in our laboratory have demonstrated that the water extract of Graptopetalum paraguayense(WGP)can protect brain tissue and various types of brain cells from ischemic injury. The impact of WGP upon the BBB permeability and the regulatory mechanism(s)might involve are yet to be clarified. β-catenin is one of the structural components of the vascular endothelial wall at the adherens junction, once entering nucleus it binds to transcription factor(TCF)to regulate a variety of downstream genes dually. The primary goal of this study was thus to know if WGP or gallic acid(GA; one of the key components of WGP)act through β-catenin to protect the structure stability and barrier property of the BBB from the ischemic injury. Three major experimental approaches include: 1)To know if the in vitro ischemic insult(glucose-oxygen-serum deprivation or GOSD)caused significant damage to two of the key cellular components of BBB, astrocytes and endothelial cells(ECs); 2)To know if WGP and GA protected the BBB from the GOSD-induced injury; 3)To clarify under the GOSD stress, if WGP and GA rely on β-catenin to protect survival of the astrocytes and ECs and the barrier property of BBB and to regulate the protein expression of angiogenesis and vascular endothelial growth factor(VEGF), two of blood vessel regulatory proteins. Briefly, the in vitro ischemia model(GOSD)and the in vitro BBB cellular model were used as two major experimental platforms, and DAQZ(β-catenin inhibitor)was used to estimate the possible involvement of β-catenin in WGP or GA-mediated BBB protection. Analytic assays used in the study include, the trypan blue dye exclusion assay, immunocytochemistry, double immunocytochemistry/immunofluorescence (ICC/IF) staining assay, the Western blot analysis and the astrocyte-endothelial adhesion assay. The current results showed that GOSD significantly increased the BBB permeability, inhibited survival of astrocyte and brain ECs, and decreased the total amount but increased the nuclear translocation of β-catenin in both astrocytes and ECs, indicating GOSD may act through nuclear β-catenin to regulate the gene expression. Low-dose WGP and GA(0.1 μM) can both increase total amount of β-catenin in GOSD-treated astrocytes and ECs to block the GOSD-increased BBB permeability, cell death of both cell lines and the adherence of astrocytes to ECs. WGP- or GA-increased β-catenin appeared to phosphorylate(or activate)ERK/1/2 or AKT to protect the survival of GOSD-treated astrocytes or ECs. WGP also appeared to rely on β-catenin to stimulate the protein expression of Ang-1 but inhibit that of VEGF in GOSD-treated ECs, whereas GA appeared to act through β-catenin to stimulate the protein expression of Ang-1 in GOSD-treated astrocytes, all together could protect the barrier property of BBB. It is worth to mention that WGP also inhibited the VEGF expression in GOSD-treated astrocytes that however, was β-catenin independent but could also protect the function of BBB. In overall, the study has demonstrated for the first time that WGP and GA could protect BBB from ischemia(GOSD)-induced injury; and WGP and GA relied on β-catenin to protect survival of the GOSD astrocytes and ECs(ERK and AKT dependent)and the barrier property of blood vessels(by stimulating Ang-1 but inhibiting VEGF expression). WGP and GA also stimulated astrocyte adherence to EC that could also stabilize BBB structure but whether depends on β-catenin or not still remains to be determined. All the results can further strengthen our knowledge about the mechanisms underlying the WGP-mediated brain protection against cerebral ischemia and to increase the therapeutic value of WGP in stroke.
中文摘要 i
Abstract ii
目錄… iv
圖目錄… vii
壹、前言 .1
一、腦中風 1
(一)腦中風之種類及治療 1
(二)缺血性腦中風的致病機轉 2
(三)腦缺血之研究模式 3
二、血腦障壁 3
(一)血腦障壁之功能 3
(二)血腦障壁之組成及其調節因子 4
(三)缺血性腦中風對血腦障壁的傷害及治療 5
(四)血腦障壁體外研究模式介紹 5
三、β-連環蛋白(β-catenin) 6
(一)β-catenin 蛋白的結構及功能 6
(二)β-catenin在血腦障壁扮演的角色 7
(三)β-catenin對BBB相關基因(VEGF、Ang-1、MMPs)生成之
調控 8
四、石蓮花 8
(一)石蓮花之功效 8
(二)石蓮花水萃物對缺血腦組織及腦細胞之保護 9
(三)沒食子酸 9
五、研究動機與目標 10
貳、實驗材料與方法 11
一、藥品與試劑 11
二、實驗動物 14
三、動物繁殖 14
四、細胞培養 14
(一)初代神經膠質細胞的純化(微膠細胞/星芒狀細胞) 14
(二)初代大腦內皮細胞培養 15
五、體外細胞缺血模式 16
六、體外血腦障壁模式建立及通透性評估 16
七、BBB模組通透性之評估 (Evan''s blue extravasation assay) 16
八、細胞加藥處理 17
(一)石蓮花水萃物(Water extract of Graptopetalum paraguayense/WGP) 17
(二)沒食子酸(Gallic acid/GA) 17
(三)2.4-diamino quinazoline(DAQZ,β-catenin抑制劑) 18
九、蛋白萃取及濃度測定 18
(一)總蛋白萃取 18
(二)蛋白濃度測定 18
十、西方墨點法 19
(一)SDS-PAGE(SDS-膠體電泳) 19
(二)半乾式蛋白轉漬 19
(三)免疫雜交 20
(四)顯影及蛋白定量 20
十一、台盼藍染色(Trypan blue dye exclusion assay):細胞存活分析 20
十二、細胞免疫化學染色 21
十三、細胞免疫螢光染色 21
十四、統計分析 22
參、結果 23
一、初代星芒狀細胞及大腦內皮細胞之純度鑑定 23
二、GOSD處理明顯提升體外BBB細胞模具之通透性 23
三、GOSD處理明顯抑制星芒狀細胞細胞的存活及β-catenin的蛋白表現量 23
四、GOSD處理明顯抑制大腦內皮細胞的存活及β-catenin的蛋白表現量 24
五、WGP(低劑量)和GA(0.1 μM)可透過β-catenin有效抑制被GOSD提升的BBB通透性 24
六、低劑量WGP和GA(0.1μM)可以透過提升β-catenin的蛋白總表現量有效提升GOSD壓力下星芒狀細胞的存活 25
七、低劑量WGP和GA(0.1μM)均可透過β-catenin促進GOSD星芒狀細胞中ERK 的活化;但只有前者可透過β-catenin活化AKT 26
八、低劑量WGP可藉由提升β-catenin的蛋白總表現量來抑制GOSD星芒狀細胞Ang-1之表現;而GA(0.1μM)則藉由提升β-catenin來提升Ang-1之表現 26
九、低劑量WGP可藉由提升GOSD大腦內皮細胞的β-catenin來促進ERK及AKT的活化,並提升Ang-1但抑制VEGF的蛋白表現 27
十、WGP及GA可以增加GOSD壓力下的星芒狀細胞對大腦內皮細胞的黏附性 28
肆、討論 29
一、WGP對GOSD壓力下星芒狀細胞存活的保護以中、低劑量為限,但僅低劑量之保護與β-catenin有關 29
二、WGP和GA對BBB同樣具保護性但兩者利用的訊號路徑和保護機轉並不完全相同 30
三、WGP與GA可藉由對β-catenin蛋白表現量的提升,保護缺血壓力下BBB之功能 31
四、GOSD對VEGF及、Ang-1蛋白表現量的影響,隨時間及細胞種類而異,WGP及GA明顯抑制VEGF但提升Ang-1之表現,可藉此鞏固缺血壓力下BBB結構之穩定性 31
五、β-catenin對VEGF、Ang-1之調控 32
六、研究之重要貢獻 32
伍、參考文獻 49
一、中文文獻 49
二、西文文獻 50
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