English  |  正體中文  |  简体中文  |  全文筆數/總筆數 : 29490/55136 (53%)
造訪人次 : 1994388      線上人數 : 461
RC Version 7.0 © Powered By DSPACE, MIT. Enhanced by NTU Library IR team.
搜尋範圍 查詢小技巧:
  • 您可在西文檢索詞彙前後加上"雙引號",以獲取較精準的檢索結果
  • 若欲以作者姓名搜尋,建議至進階搜尋限定作者欄位,可獲得較完整資料
  • 進階搜尋
    主頁登入上傳說明關於CMUR管理 到手機版
    請使用永久網址來引用或連結此文件: http://ir.cmu.edu.tw/ir/handle/310903500/58579


    題名: 植物性雌激素藉由雌激素受體改善阿黴素誘發之心臟毒性並穩定HSF1 而抑制胰島素生長因子接受器凋亡路徑
    Phytoestrogens ameliorates Doxorubicin-Induced Cardiomyotoxicity via Estrogen Receptor-α/β and Stabilizes HSF1 to Inhibit the IGF-IIR Apoptotic Pathway
    作者: 黃佩真;Pei-Chen Huang
    貢獻者: 臨床醫學研究所博士班
    關鍵詞: 阿黴素;花青素;類胰島素生長因子II 訊息傳導;細胞凋亡;雌激素受體;心肌細胞;阿黴素;漆黃素;類胰島素生長因子II 訊息傳導;細胞凋亡;雌激素受體;心肌細胞;doxorubicin;anthocyanin;IGF-IIR signaling;apoptosis;estrogen receptors;cardiomyocyte;Doxorubicin;Fisetin;IGF-IIR signaling;apoptosis;estrogen receptors;cardiomyocyte
    日期: 2018-06-26
    上傳時間: 2018-12-25 10:38:05 (UTC+8)
    出版者: 中國醫藥大學
    摘要: 第一部分
    阿黴素(Doxorubicin, Dox)廣泛用於治療不同類型的癌症。但因其對心臟具有毒性,故使用上有劑量限制,而影響療效。我們先前的研究發現Dox 透過向下調控熱休克因子1
    ( heat shock factor 1, HSF1) 路徑誘導類胰島素生長因子II 受體(insulin-like growth factor II
    receptor, IGF-IIR)累積,進而導致心肌細胞凋亡。在本研究中,我們證明了一項新的機制
    -花青素 (anthocyanin, ACN) 保護心肌細胞免於Dox 所誘導的心臟損傷。我們發現ACN透過雌激素受體降低IGF-IIR 表現並穩定HSF1 進而抑制caspase 3 活化和心肌細胞凋亡。
    因此,來自植物的植物性雌激素已被認為是一種治療心臟衰竭的潛在療法。據報導天然化合物ACN 能夠降低心血管疾病(cardiovascular disease , CVD)的風險。本研究證實花青
    素作為一種保護心臟的藥物,對抗Dox所誘導的心臟衰竭;花青素藉由雌激素受體來穩定HSF1 的表現並向下調節IGF-IIR 誘導的心肌細胞凋亡作用。
    第二部分
    癌症排名世界十大死因第二位,僅次於心血管疾病之後。阿黴素是一種抗癌藥物,但其會導致氧化壓力的產生,造成健康組織損傷。由於雌激素活性的保護作用,男性比女性
    更容易發生心臟功能障礙。然而,停經後的女性和早期卵巢切除的女性患有缺血性心臟病和心肌梗塞的風險增加。雌激素不足會惡化心血管功能障礙並增加心臟衰竭的可能性。我
    們先前的研究證明IGF-IIR 表現增加是造成心臟毒性的主要原因。因此,抑制IGF-IIR 訊息傳導路徑或許能夠成為新的標靶來減緩Dox誘導的心臟毒性進而預防心肌梗塞。在這項
    研究中,我們試圖透過靶向IGF-IIR 訊號傳導途徑和活化雌激素受體來探討漆黃素 (Fisetin)
    的心臟保護作用。漆黃素作為一種Dox所誘導的心肌細胞和卵巢切除大鼠的心臟組織中微
    弱的雌激素。實驗結果發現,漆黃素透過活化ERα/β 訊息傳導和抑制IGF-IIR 訊息傳導途徑來減緩心臟細胞凋亡。為了防止Dox 誘發H9c2 細胞中的心臟毒性,我們發現漆黃素活
    化CHIP 和SIRT-1 蛋白進而穩定HSF1,並以劑量依賴性方式 (dose dependent manner)增加心肌細胞存活率。令人驚訝的是,我們觀察到漆黃素具有緩解心臟毒性和增加存活蛋白表
    現的能力。然而,ER 拮抗劑(ICI 182780)活化IGF-IIR 訊號,進而增加活化的caspase 3 蛋白活性。此外,我們還探討了漆黃素對短期去卵巢大鼠的保護作用。我們使用8 週齡的
    WKY 雌性大鼠,並隨機分成5 組,分別為對照組 (control)、阿黴素處理組 (Dox)和雙側卵巢切除組 (OVX)、Dox 處理且OVX組 (Dox + OVX)以及Dox 處理且用Fisetin 治療組 (Dox+
    OVX+ Fisetin)。我們利用手術的方式完成卵巢切除。有趣的是,研究結果顯示漆黃素提高了心臟組織中細胞存活蛋白pAKT 和促細胞存活蛋白質如Bcl-xL 和Bcl-2 的表現。另外,
    漆黃素處理,除了改善Dox 和Dox-OVX 組之心臟特徵如:體重、全心重量和左心室重量以外, 心臟功能評估指標如: 射血分數(Ejecton fraction, EF)和短縮分率(Fractional
    shortening, FS)也被改善至正常值。在漆黃素處理的Dox-OVX 心臟組織中,其改善了組織結構,減少了膠原蛋白沉積和心臟組織間隙並減緩Dox處理下由於心臟重塑所造成的細胞
    凋亡作用。因此,漆黃素可能是一種有潛力的藥物,可以降低Dox引起的心臟毒性,並對停經後的婦女或是卵巢切除的婦女提供心臟保護作用。
    Part 1

    Doxorubicin (Dox) is extensively used for chemotherapy in different types of cancer, but its use is limited to because of its cardiotoxicity. Our previous studies found that doxorubicin-induced insulin-like growth factor II receptor (IGF-IIR) accumulation causes cardiomyocytes apoptosis via down-regulation of HSF1 pathway. In these studies, we demonstrated a new mechanism through which anthocyanin protects cardiomyoblast cells against doxorubicin-induced injury. We found that anthocyanin decreased IGF-IIR expression via estrogen receptors and stabilized heat shock factor 1 (HSF1) to inhibit caspase 3 activation and apoptosis of cardiomyocytes. Therefore, the phytoestrogen from plants has been considered as another potential treatment for heart failure. It has been reported that the natural compound anthocyanin (ACN) has the ability to reduce the risk of cardiovascular disease (CVD). Here, we demonstrated that anthocyanin acts as a cardioprotective drug against doxorubicin-induced heart failure by attenuating cardiac apoptosis
    via estrogen receptors to stabilize HSF1 expression and down-regulated IGF-IIR-induced cardiomyocyte apoptosis.

    Part 2
    Cancer is a second leading cause of death after the cardiovascular disease in the world. Unfortunately, Doxorubicin an anticancer drug leads to generation of oxidative stress and thus causes the damage to healthy tissues. Cardiac dysfunction is more common in male than female due to protective effect of estrogenic activity. However, post- menopausal woman and early ovariectomized females have increased risk of ischemic heart disease and myocardial infarction.
    Deficiency of estrogen worsens cardiovascular dysfunction and increases the possibility of heart failure. Our previous studies have demonstrated that upregulation of the IGF-IIR (Insulin-like growth factor II receptor) is the leading cause of cardiotoxicity. Thus, suppression of IGF-IIR signaling pathway may be a novel target to suppress the Dox-induced cardiotoxicity and thus to prevent myocardial infarction. In this study, we tried to explore that cardio-protective activity of Fisetin, a slightly weak estrogen in Dox induced cardiomyocytes and ovariectomized heart tissues by targeting the IGF-IIR signaling pathway and activation of estrogen receptors. We found that Fisetin alleviated the cardiac apoptosis via ERα/β signaling and inhibited IGF-IIR signaling pathway. Fisetin, to prevent dox stimulated cardiotoxicity in H9c2 cardiomyoblast cells and we found that fisetin provided the HSF 1 stability via CHIP and SIRT-1 activation and thus increased the cell survival in dose dependent manner. Surprisingly we observed that fisetin has the ability to alleviate the cardiotoxicity and increased the expression of survival proteins. Moreover, ER antagonist ICI 182780 activated IGF-IIR expression thus increased the cleaved caspase3 activity.
    Furthermore, we also checked the protective role of fisetin in short term ovariectomized rats. For this, we included eight week old WKY female rats and divided randomly in five groups’viz.Control, Doxorubicin treated female rats and bilateral ovariectomized female rats as OVX, Dox treated OVX and Dox treated Ovariectomized with Fisetin. Ovariectomy was done by surgical
    method. Interestingly, as per our findings we observed that fisetin elevated the expression level of cellular survival markers pAKT, and pro-survival proteins like Bcl-xL and Bcl-2 in cardiac tissue
    samples. Additionally, the cardiac characteristics viz. EF (Teich) and FS% were also improved to normal level when treated with fisetin in addition to body weight, whole heart weight and left
    ventricle weight in Dox induced ovariectomized rats. In Dox –OVX group heart tissues treated with fisetin, it improved the tissue architecture, reduced the collagen deposition and interstitial
    spaces with less number of TUNEL positive cells which were developed due to cardiac remodeling during dox treatment compared to Dox and Dox –OVX group. Therefore, we conclude that fisetin
    can be a promising agent to minimize stress induced cardiotoxicity and can increase the survival rate in bilateral ovariectomized female rats.
    顯示於類別:[臨床醫學研究所] 博碩士論文

    文件中的檔案:

    檔案 大小格式瀏覽次數
    index.html0KbHTML29檢視/開啟


    在CMUR中所有的資料項目都受到原著作權保護.

    TAIR相關文章

     


    DSpace Software Copyright © 2002-2004  MIT &  Hewlett-Packard  /   Enhanced by   NTU Library IR team Copyright ©   - 回饋