臺灣博碩士論文加值系統

大花紅景天(RC)是傳統中草藥，此藥物有抗發炎的效果。探討大花紅景天(RC)及紅景天萃取物Salidroside (S)對慢性間歇低氧心肌凋亡動物model C57BL/6J小黑鼠心肌保護機制作用。故本研究評估此藥用植物大花紅景天(RC) 及紅景天萃取物Salidroside (S)對人類慢性間歇低氧心肌之保護效果，並探討其保護預防機制。目的觀察紅景天保護慢性間歇低氧心肌凋亡OSA低氧心肌凋亡。紅景天(Rhodiola)對慢性間歇低氧(CIH) 心肌凋亡作用仍未知。探討大花紅景天(RC)及紅景天萃取物對慢性間歇低氧心肌凋亡動物model C57BL/6J小黑鼠心肌保護機制作用。方法：六十四支5-6個月大C57BL/6J老鼠分四組。控制組RC model組及紅景天萃取物 (Salidroside, S) S model組老鼠第一個月給予正常氧氣(Control)(控制組, 21%氧氣, n=16支) 然後第二個月曝露在正常氧氣和胃管餵食鹽水。低氧組RC model組及紅景天萃取物 (Salidroside,S) S model老鼠慢性間歇低氧(Hypoxia)(低氧組) ，第一個月每天7%氧氣60秒，20%氧氣60秒交替，8小時，第二個月低氧結合每天胃管餵食鹽水5毫克每公斤，每組數n=16支四個星期) 低氧+90RC組和低氧+270RC組(Hypoxia+90RC and Hypoxia+270RC group) 及紅景天萃取物 (Salidroside, S) S model組低氧+10S組和低氧+30S組(Hypoxia+10S and Hypoxia+30S group)第一個月曝露慢性間歇低氧，然後第二個月每天低氧結合口部胃管餵RC (大花紅景天Rhodiola Crenulata) 90毫克每公斤和RC 270毫克每公斤(每組數n=16支) RC model組及紅景天萃取物 (Salidroside, S) S model組第一個月曝露慢性間歇低氧，然後第二個月每天低氧結合口部胃管餵S (紅景天萃取物 (Salidroside, S) S model 10毫克每公斤和S 30毫克每公斤(每組數n=16支)。離體心臟測量心臟重指標，免疫螢光染色(H&E staining), TUNEL 陽性檢測方法(TUNEL-positive assays)和西方墨點法 (Western Blotting). 結果:顯示大花紅景天(RC) RC model組及紅景天萃取物 (Salidroside, S) S model組作用保護慢性間歇低氧誘導心肌凋亡C57BL/6J小黑鼠。由實驗結果可明顯觀察到顯示大花紅景天(RC) RC model組及紅景天萃取物 (Salidroside, S) S model組保護慢性間歇低氧誘導心肌凋亡C57BL/6J小黑鼠作用。發現顯示大花紅景天 (RC) RC model組及紅景天萃取物 (Salidroside, S) S model 組保護慢性間歇低氧誘導心肌凋亡C57BL/6J小黑鼠作用。討論 : 研究結果建議與控制組比較大花紅景天(RC)及紅景天萃取物(S)改進 C57BL/6J小黑鼠誘導慢性間歇低氧心肌Fas-依賴凋亡途徑(Fas-dependent apoptotic pathways) 和 線粒體-依賴凋亡途徑(mitochondria-dependent apoptotic pathways). Compared with control, Hypoxia treatment 大花紅景天RC及紅景天萃取物(S)可保護慢性間歇低氧動物模型心肌凋亡，結果建議紅景天RC及紅景天萃取物S保護OSA睡眠呼吸暫止低氧心肌凋亡，大花紅景天RC及紅景天萃取物S可減輕睡眠呼吸慢性間歇低氧心肌障礙，降低心血管疾病致死危險性。

Background. The goal of this study is to determine if Rhodiola Crenulata (RC) and Salidroside have protective effects on mice hearts with severe sleep apnea model. Methods. Sixty-four C57BL/6J mice 5-6 months old were distributed into 4 groups i.e. Control group (21% O2, 24 hrs per day, 8 weeks, n=16); Hypoxia group (Hypoxia: 7% O2 60 seconds, 20% O2 alternating 60 seconds, 8 hrs per day, 8 weeks, n=16); Model RC : Hypoxia+90RC and Hypoxia+270RC group (Hypoxia for 1st 4 weeks and hypoxia pretreated 90mg/kg and 270mg/kg Rhodiola Crenulata by oral gavage per day for 2nd 4 weeks, each n=16). Model S : Hypoxia+S10 and Hypoxia+S30 group (Hypoxia for 1st 4 weeks and hypoxia pretreated 10mg/kg and 30mg/kg Salidroside by oral gavage per day for 2nd 4 weeks, each n=16). Excised hearts from 4 groups of mice were analyzed for heart weight index changes using H&E staining, TUNEL-positive assays and Western Blotting protein. Results. Cardiac widely dispersed TUNEL-positive apoptotic cells in mice hearts were less in Hypoxia with Rhodiola Crenulata treatment, Hypoxia with Salidroside treatment than those in Hypoxia. Compared with Hypoxia, the protein levels of Fas ligand, Fas death receptors, Fas-Associated Death Domain (FADD), activated caspase 8, and activated caspase 3 (Fas dependent apoptotic pathways) were decreased in Hypoxia with Rhodiola Crenulata treatment, Hypoxia with Salidroside treatment. The protein levels of Bad, Bax, t-Bid, activated caspase 9, activated caspase 3 (mitochondria dependent apoptotic pathway) were less in Hypoxia with Rhodiola Crenulata treatment, Hypoxia with Salidroside treatment than those in hypoxia. The protein levels of Bcl2, Bcl-xL, p-Bad (Bcl2-realted anti-apoptotic pathway) and VEGF, p-PI3k, p-AKT (VEGF-related pro-survival pathway) were higher in Hypoxia with Rhodiola Crenulata treatment than those in hypoxia. Conclusions. Our findings suggest that Rhodiola Crenulata and Salidroside herb-related anti-oxidant agents have protective effects on chronic intermittent hypoxia-induced cardiac apoptosis via Fas-dependent and mitochondria-dependent apoptotic and VEGF-related pro-survival pathway, which might be a influential candidate for developing an optional therapy for OSA.

Contents
Chapter 1 Introduction............................................................................1
1.1 Motivation............................................................................................1
1.2 Obstructive Sleep Apnea (OSA)..........................................................1
1.3 Chronic intermittent hypoxia (CIH)...................................................1
1.4 Rhodiola Crenulata.............................................................................2
1.5 Salidroside herb-related anti-oxidant agents.…..…............…..…….2
1.6 Apoptosis.......................................................................................3
Chapter 2 Materials and Methods .........................................................7
2.1 Animal model......................................................................................7
2.2 Rhodiola Crenulata and Salidroside herb anti-oxidant agents……8
2.2.1 Rhodiola Crenulata extraction process................................8
2.2.2 Salidroside herb anti-oxidant agents extraction process…8
2.3 Echocardiography................................................................................9
2.4 Cardiac characteristics.........................................................................9
2.5 Tissue Extraction................................................................................10
2.6 Electrophoresis and Western Blot......................................................10
2.7 H&E staining, Masson Trichrome Staining, and TUNEL…..……11
2.8 Statistical analysis............................................................................12
Chapter 3 Results...................................................................................13
3.1 Body weight and cardiac characteristics...........................................13
3.1.1 Body weight and cardiac characteristics with RC....................13
3.1.2 Body weight and cardiac characteristics with S....................14
3.2 Cardiac histopathological changes of left ventricle..........................16
3.3 TUNEL-positive apoptotic cells of left ventricle .............................17
3.4 Cardiac Fas receptor dependent apoptotic pathways……….….……18
3.4.1 Cardiac Fas receptor dependent apoptotic pathways with RC…18
3.4.2 Cardiac Fas receptor dependent apoptotic pathways with S…20
3.5 Cardiac mitochondrial-dependent apoptotic pathways……..………22
3.5.1 Cardiac mitochondrial-dependent apoptotic pathways with RC....22
3.5.2 Cardiac mitochondrial-dependent apoptotic pathways with S…27
3.6 Mediator from Fas to mitochondrial pathway…………….………27
3.7 Cardiac Fas and mitochondrial dependent apoptosis………………29
3.7.1 Cardiac Fas and mitochondrial dependent apoptosis with RC…29
3.7.2 Cardiac Fas and mitochondrial dependent apoptosis with S…31
3.8 Cardiac VEGF-related pro-survival pathway…………..…………33
Chapter4 Discussion...............................................................................36
4.1 Major findings……………………………………..………………36
4.2 Experimental Design……………………………………….………41
4.3 Hypothesized clinical application…………………….……………46
Chapter5 Conclusion………………..…………………………………48
Reference………………………………………………………………51
Abstract in Chinese……………………………………………………58
謝辭..........................................................................................................61






Figures

Fig 3.1 H&E, Masson trichrome, TUNEL assay, DAPI with RC............19
Fig 3.2 H&E, Masson trichrome, TUNEL assay, DAPI with S...............21
Fig 3.3 Fas receptor dependent apoptotic pathways with RC.................23
Fig 3.4 Fas receptor dependent apoptotic pathways with S.....................24
Fig 3.5 Mitochondrial-dependent apoptotic pathways with RC...............26
Fig 3.6 Mitochondria-dependent apoptotic pathways with S.................. 28
Fig 3.7 Mediator from Fas to mitochondrial pathway.............................30
Fig 3.8 Fas and mitochondrial dependent apoptosis with RC..................32
Fig 3.9 Fas and mitochondrial dependent apoptosis with S.....................34
Fig 3.10 VEGF-related pro-survival pathway..........................................35
Fig 4.1 Fas, mitochondria and VEGF-related pathway with RC.............39
Fig 4.2 Fas and mitochondrial-dependent apoptotic pathways with S....40
Fig 5.1 Cardiac apoptotic and pro-survival pathways..............................50








Tables

Table 3.1 Body weight and cardiac characteristics with RC...................15
Table 3.2 Body weight and cardiac characteristics with S..................17

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