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研究生:鄭惟元
研究生(外文):Wei-Yuan Cheng
論文名稱:以ApoE基因剔除小鼠模式評估克弗爾肽延緩骨質流失與心血管疾病之功效
論文名稱(外文):Effects of Kefir-fermented peptides for the attenuation of bone loss and cardiovascular disease in ApoE knockout mice model
指導教授:陳全木陳全木引用關係陳小玲陳小玲引用關係
口試委員:范洪春鄭旭辰
口試日期:2019-01-29
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:2019
畢業學年度:107
語文別:中文
論文頁數:122
中文關鍵詞:心血管疾病骨質流失血管鈣化氧化型低密度脂蛋白ApoE-/-小鼠炎症反應克弗爾肽
外文關鍵詞:cardiovascular diseasesbone lossvascular calcificationox-LDLApoE-/- miceinflammationkefir peptides
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心血管疾病與骨質流失傳統上被視為是兩種獨立且彼此不具關聯性的退化性慢性病,然而這兩種疾病的關聯性於近幾年的研究中陸續被闡明,高脂血症為心血管疾病的主要危險因子,會增加動脈粥狀硬化的風險,嚴重時甚至會引發血管鈣化,有趣的是,高脂血症也會大幅增加罹患骨質疏鬆症的風險,而主動脈鈣化即為同時罹患心血管疾病與骨質疏鬆症的患者最常見的病理現象,當心血管疾病的患者在服用鈣補充品進行骨骼保健時,容易導致鈣質沉積於血管引發血管鈣化,反而會加劇心血管疾病病況,因此能同時針對心血管疾病與骨質流失這兩種慢性疾病的預防與治療策略至關重要。先前的研究指出,克弗爾對人體具有多種的益處,而本實驗室自行研發的克弗爾肽於前人的研究中分別對於心血管疾病與骨質疏鬆症皆具有延緩病情的效果。故本實驗進一步使用ApoE-/-小鼠模擬高脂血症患者,欲探討克弗爾肽是否能在延緩骨質流失的同時對於心血管也具有保護效果。研究中使用7週齡ApoE-/-小鼠作為實驗動物,其遺傳背景B6小鼠作為正常型對照組,給予正常飼料的B6小鼠與ApoE-/-小鼠分別作為:(1)正常型對照組(Wile type);(2)實驗控制組(Control);再將以致動脈粥狀硬化飼料誘發高脂血症的ApoE-/-小鼠分為四個組別:(3)疾病組(Mock);(4)克弗爾肽低劑量組(Kefir low dose);(5)克弗爾肽高劑量組(Kefir high dose);(6)市售降血脂藥物組(Atorvastatin),進行為期13週的實驗後犧牲小鼠,採集小鼠血液、心臟、血管、股骨等組織進行分析,評估克弗爾肽延緩心血管疾病與骨質流失的效果。由血液生化分析結果顯示,克弗爾肽能降低血液中ox-LDL與TNF-α含量,並提升骨生成指標PINP,降低骨吸收指標CTXI;此外,克弗爾肽也能降低主動脈TNF-α與IL-1β蛋白表現量,減少血管炎症反應;由心臟主動脈竇病理切片結果顯示,克弗爾肽能延緩動脈粥狀硬化塊的形成、降低血管纖維化以及減少鈣鹽沉積;藉由微電腦斷層掃描分析股骨的結果顯示,克弗爾肽能有效降低骨小樑間分離率,並提升骨小樑厚度,同時抑制骨小樑型態向桿狀轉變,此外克弗爾肽也能顯著提升皮質骨骨量與強度,以及增加皮質骨骨礦物密度。綜合上述結果,克弗爾肽可以透過減少血液中的氧化脂質來降低全身性與主動脈的炎症反應,藉此可以促進骨生成作用並抑制骨吸收作用,同時也能延緩心血管疾病發展,因此有潛力作為高脂血症患者對於骨骼與心血管的保健產品。
Cardiovascular diseases and bone loss are chronic degenerative diseases which have been considered to be independent pathway traditionally. In recent years, growing evidences indicated that the association between these two chronic diseases. hyperlipidemia is the dominant risk of cardiovascular disease that caused atherosclerosis, seriously, it will cause vascular calcification, interestingly, hyperlipidemia also be a risk factor of osteoporosis. Aortic calcification is a pathological performance often exists in patients with both cardiovascular diseases and osteoporosis. It is easier to make calcium deposit in blood vessels to aggravate cardiovascular diseases when patients with cardiovascular diseases take calcium-rich healthy food for healthy bone. Therefore, it is necessary to make a plan of prevention and treatment for both cardiovascular disease and bone loss. The studies have been demonstrated that kefir has various benefit for human. In our previous studies, kefir peptides which developed by our laboratory has efficacy for attenuation of cardiovascular diseases and osteoporosis respectively. In this study, B6:129P2-Apoetm1Unc/J knockout mice was used to imitate patient with hyperlipidemia to investigate whether kefir peptides can attenuate bone loss and cardiovascular diseases simultaneously. The 7-week-old ApoE-/- mice were used as experimental animal and C57BL/6 mice at the same age were used as a wild-type normal control. C57BL/6 mice and ApoE-/- mice were placed on a chow diet and divided into two groups:(1) Wile type;(2) Control;ApoE-/- mice were placed on an atherogenic diet and divided into four groups:(3) Mock;(4) Kefir low dose;(5) Kefir high dose;(6) Atorvastatin. After 13 weeks treatment, the tissue sample including serum, heart, aorta, and femur were collected for analysis. In the blood biochemical examinations, result showed that the administration of kefir peptides can decrease the levels of ox-LDL and TNF-α as well as the levels of CTXI and increasing the levels of PINP. Moreover, the administration of kefir peptides also decrease inflammation in aorta by decreaseing the expression of TNF-α and IL-1β. Aortic sinus pathological section results revealed that kefir peptides treatment groups had less the formation of atherosclerosis plague and fibrosis as well as the deposition of calcium. The micro-CT analysis indicated that kefir peptides treatment groups had lower trabecular separation and higher trabecular thickness as well as inhibiting the transformation of trabecular pattern to rod-shaped. Moreover, kefir peptides treatment groups also had higher cortical bone mass, strength and cortical bone mineral density. In conclusion, Kefir peptides can lower the inflammation of systemic and aorta by reducing the oxidized lipids in the blood, thereby promoting bone formation and inhibiting the bone resorption. Additionally, it can attenuate the development of cardiovascular disease. Therefore, it has the potential to be a healthy food for patients with hyperlipidemia to protect bone and cardiovascular.
中文摘要 i
Abstract ii
目錄 iv
表次 vii
圖次 viii
壹、緒論 1
貳、文獻探討 2
一、心血管疾病 2
(一) 常見之心血管疾病與成因 2
(二) 心血管疾病風險因子 2
二、高脂血症 3
(一) 脂蛋白 (Lipoproteins) 3
(二) 高脂血症分類 7
三、動脈粥狀硬化 8
(一) 動脈粥狀硬化病程 8
(二) 動脈粥狀硬化動物模型 10
(三) 動脈粥狀硬化藥物 13
四、血管鈣化 14
(一) 血管鈣化成因 14
(二) 血管鈣化動物模型 16
(三) 血管鈣化治療 16
五、骨質疏鬆症 17
(一) 骨骼結構 17
(二) 骨骼組成 18
(三) 骨骼重塑作用 22
(四) 骨質疏鬆症分類 24
(五) 骨質疏鬆症治療 25
六、心血管疾病與骨質疏鬆症之關聯性 28
七、生物醫學影像與生物材料機械性質分析 30
(一) 生物醫學影像之發展 30
(二) 電腦斷層掃描(Computerized tomography, CT) 30
八、克弗爾發酵產物及其保健應用 33
(一) 克弗爾的由來 33
(二) 克弗爾的組成 33
(三) 克弗爾的保健功效 35
九、研究動機 38
參、材料與方法 39
一、實驗動物之品系 39
(一) 實驗動物品系來源與飼養 39
(二) ApoE基因剔除小鼠建構與基因分析 39
(三) 動物模式性別分析 40
二、實驗流程 40
(一) 實驗規劃 40
(二) 動物模式建立 40
(三) 動物試驗設計與分組 40
(四) 管餵材料製備 41
(五) 犧牲前準備 41
(六) 動物犧牲與樣品採集 41
三、血液生化數值測定 44
(一) 愛德士生化分析儀(VetTestTM)測定項目 44
(二) 分析套組測定項目 44
四、心臟組織冷凍切片染色 45
(一) 冷凍切片前處理 45
(二) 蘇木精和伊紅染色(hematoxylin & eosin stain, H&E) 46
(三) 油紅染色(Oil red-O stain) 47
(四) 馬松三色染色(masson''s trichrome stain) 48
(五) Von kossa染色 48
(六) 免疫組織化學染色(immunohistochemistry, IHC) 49
五、主動脈蛋白表現分析 50
(一) 總蛋白萃取 50
(二) 蛋白濃度定量 50
(三) 西方墨點轉漬法 50
六、微電腦斷層掃描(Micro Computed Tomography, Micro-CT) 55
(一) Micro-CT分析 55
(二) 近膝關節之遠端股骨骨小樑與皮質骨骨微結構分析 56
(三) 骨微結構影像重組 58
七、統計分析及繪圖軟體 59
肆、結果 60
一、小鼠生理健康之參數與血液生化數值 60
(一) 小鼠體重變化量與攝食變化量 60
(二) 小鼠肝臟功能之血液生化數值分析 64
(三) 小鼠肌肉病變之血液生化數值分析 66
(四) 小鼠血液中礦物質平衡 66
二、克弗爾肽延緩心血管疾病發展之功效評估 69
(一) 小鼠血液中脂質變化之生化數值分析 69
(二) 小鼠血液中脂質氧化程度之生化數值分析 71
(三) 小鼠血液中炎症反應之生化數值分析 73
(四) 小鼠主動脈局部炎症反應分析 75
(五) 小鼠主動脈竇組織病理切片評估 77
三、克弗爾肽延緩骨質流失之功效評估 84
(一) 小鼠血液中骨質代謝之生化數值分析 84
(二) 以微電腦斷層掃描儀(Micro-CT)掃瞄並重組小鼠股骨3D結構 86
(三) 以微電腦斷層掃描儀(Micro-CT)掃瞄並分析小鼠股骨結構參數 91
伍、討論 100
一、小鼠生理健康之參數與血液生化數值 100
(一) 小鼠體重變化量與攝食變化量 100
(二) 小鼠肝臟功能之生化數值分析 100
(三) 小鼠肌肉病變之血液生化數值分析 101
(四) 小鼠血液中礦物質平衡 101
二、克弗爾肽延緩心血管疾病發展之功效評估 102
(一) 小鼠脂質變化之生化數值分析 102
(二) 小鼠脂質氧化程度之生化數值分析 102
(三) 小鼠炎症反應評估 102
(四) 小鼠主動脈竇組織病理切片評估 103
(五) 克弗爾肽延緩心血管疾病之機制探討 104
三、克弗爾肽延緩骨質流失之功效評估 104
(一) 小鼠血液中骨質代謝之生化數值分析 104
(二) 以微電腦斷層掃描儀(Micro-CT)掃瞄分析小鼠股骨骨微結構 105
(三) 克弗爾肽延緩骨質流失之機制探討 106
陸、結論 108
柒、參考文獻 109
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