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研究生:黃雅芝
研究生(外文):Ya-Chih Huang
論文名稱:探討正丁烯基苯酞對於糖尿病視網膜病變之保護作用及機轉
論文名稱(外文):The study for protective effect and mechanism of n-Butylidenephthalide in diabetic retinopathy
指導教授:許國堂蔡女滿
指導教授(外文):Gwo-Tarng SheuNu-Man Tsai
口試委員:廖光文廖朝財李崇仁
口試委員(外文):Kuang-Wen LiaoChao-Tsai LiaoChung-Jen Lee
口試日期:2023-07-11
學位類別:博士
校院名稱:中山醫學大學
系所名稱:醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2023
畢業學年度:111
語文別:中文
論文頁數:117
中文關鍵詞:糖尿病視網膜病變正丁烯基苯酞視網膜色素上皮細胞緊密連結抗氧化血管新生老化
外文關鍵詞:diabetic retinopathyn-butylidenephthalideretinal pigment epitheliumtight junction impairmentanti-oxidantneovascularizationsenescence
DOI:10.6834/csmu202300170
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糖尿病視網膜病變是糖尿病併發症之一,好發於中老年且造成視力受損及失明,全球和台灣發生率分別為27 % 和11.7 %,有逐漸增加的趨勢。現今,Anti-VEGF藥物為末期糖尿病視網膜病變第一線治療方式,但是針對早期糖尿病視網膜病變目前仍未有有效治療方法,因此找尋一個可以治療早期糖尿病視網膜病變發展的成分是重要的。正丁烯基苯酞 (n-butylidenephthalide, BP) 是當歸主要活性成分之一,已被證實具有許多生物活性如抗癌、抗發炎和神經保護作用。過去文獻證實BP可以有效抑制雷射或缺氧誘發之視網膜血管新生,但目前BP應用於糖尿病視網膜病變未被探討。本實驗目的為探討BP對早期糖尿病視網膜病變之保護作用及機制。結果顯示,BP藉活化Nrf-2/HO-1訊息路徑抑制ROS及粒腺體膜電位不平衡,保護細胞生長及降低其老化反應。另外於高糖壓力下,BP亦保護RPE細胞生理作用如血液視網膜屏障和視黃醇再生,且抑制血管新生作用。於動物實驗結果顯示,BP可以有效抑制高血糖並維持體重,同時活化Nrf-2/HO-1訊息路徑減少視網膜細胞凋亡和保護RPE細胞緊密連結和視黃醇再生。總結上述,BP是具有高度潛力被開發應用於治療早期糖尿病視網膜病變之佐劑或藥物。
Diabetic retinopathy (DR) is one of diabetes-related complications that causes visual impairment and blindness in adults. The prevalence of DR is 27 % in global and 11.7 % in Taiwan, which had gradually increased trend. The first-line therapy of DR is anti-VEGF drugs for advance stage; however, there are almost no effective treatments for early DR. N-Butylidenephthalide (BP) is one of the major components of Angelica sinensis that has been evidenced with various bioactivities such as anti-cancer, anti-inflammation, and neuroprotection. BP has been used to inhibit retinal neovascularization in laser- and hypoxia-induced retinopathy, but there has not studied in early DR. Thus, the aim of this study is to explore the protective effects and mechanisms of BP in early DR. The results demonstrated that BP triggered Nrf-2/HO-1 signaling pathway to inhibit high glucose-induced ROS production, mitochondrial membrane potential imbalance, and neovascularization to maintain RPE cell viability, the integrity of BRB, and retinoid regeneration capacity and reduce senescence effect. In animal experiment, BP significantly inhibited hyperglycemia effect to keep body weight. Besides, BP also reduce retina apoptosis and protected the physiologies of RPE including tight junction and retinoid regeneration. Moreover, Nrf-2/HO-1 pathway had markedly activated in retina. Therefore, BP has great potential to be developed therapeutic agents or adjuvants for early DR.
謝誌 I
中文摘要 II
英文摘要 III
目錄 IV
表目錄 VI
圖目錄 VII
縮寫表 IX
壹、緒論 1
一、 糖尿病 (Diabetes mellitus, DM) 1
二、 糖尿病視網膜病變 (Diabetic retinopathy, DR) 2
三、 糖尿病視網膜病變之相關致病機轉 4
四、 糖尿病視網膜病變現今臨床診斷及治療模式 10
五、 視網膜色素上皮細胞 (Retinal pigment epithelium, RPE) 13
六、 正丁烯基苯酞 (n-Butylidenephthalide, BP) 15
貳、研究目的與策略 18
一、 具體研究目標 18
二、 研究策略 18
參、研究目的、材料方法 19
一、前言 19
二、材料方法 19
肆、實驗結果 36
伍、討論與結論 47
陸、參考文獻 91
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