由於人類角膜內皮細胞在體內無法再生，當角膜內皮細胞密度嚴重下降時，喪失排水功能，將導致角膜的水腫及混濁，進而對視力造成威脅，嚴重者甚至喪失視力。在目前臨床上，解決角膜內皮組織病變的方法仍以角膜移植為主，然而在捐贈角膜短缺的情況及移植後所引起的相關併發症下仍有許多患者無法被治癒。儘管有些患者能進行移植手術，但由於角膜本身品質不佳或移植後接縫處發生炎症、免疫排斥反應等原因，可能導致供體角膜內皮細胞密度大幅下降，導致移植失敗。因此，若能開發出一藥物術前對欲移植的角膜內皮細胞起到保護作用以預防移植後的發炎環境或術後能大力減少併發症發生的機會，進而有效解決角膜捐贈問題或降低手術失敗風險。本論文擬利用一氧化氮載體DNIC作為治療潛力藥物，期望能藉由一氧化氮在調節生理機制上的重要作用，如血管擴張、神經訊息傳導、調節細胞因子等，對移植細胞產生保護作用並降低移植後的發炎環境，以改善細胞存活率，並進一步提升移植成功率。
實驗中，我們合成Dinitrosyl Iron Complex (DNIC)作為一氧化氮載體，可以延長一氧化氮在生物體內的半衰期與增加傳遞距離。透過延長一氧化氮在細胞內的時間以提升一氧化氮在體內的生物可利用率。實驗結果展現DNIC在HSFM有/無添加2% FBS及50 mg/mL BSA的穩定性，以此為基礎DNIC的細胞攝取和其在細胞內的釋放動力學則透過EPR光譜與NO specific probe (DAF-FM)進一步評估，結果顯示DNIC在細胞內釋放一氧化氮的機制能提供更穩定且有效率的一氧化氮遞送能力。在細胞存活率實驗中，DNIC能夠對角膜內皮細胞B4G12起到增生作用，並且在模擬氧化壓力的體外實驗裡，DNIC預處理可有效提昇角膜內皮細胞的存活比例。綜述以上實驗結果，我們認為DNIC有潛力用於角膜移植前對供體角膜產生細胞保護作用，進而提昇細胞在惡劣環境中的生存能力，於術後DNIC具有抗發炎、抗氧化的能力下，同時促進移植後傷口的癒合且降低併發症發生機率。

Since human corneal endothelial cells cannot regenerate in the body, when the density of CECs is severely reduced, the loss of drainage function will lead to corneal edema and cloudiness, which will threaten vision and even loss of vision in severe cases. Currently, the main clinical solution for corneal endothelial lesions is corneal transplantation, however, many patients are not cured due to the shortage of donor corneas and the associated complications after transplantation. Although some patients are able to undergo transplantation, the donor corneal endothelial cell density may be significantly reduced due to poor quality of the cornea or post-transplantation inflammation or immune rejection, resulting in graft failure. Therefore, if a drug can be developed to protect the endothelial cells of the donor cornea before surgery to prevent the inflammatory environment after transplantation or after surgery, the chance of complications can be greatly reduced, which can effectively solve the problem of corneal donation or reduce the risk of surgical failure. Herein, to overcome these challenges, we developed the nitric oxide carrier DNIC as a potential therapeutic agent, hoping to improve cell survival and further enhance graft success through the important role of nitric oxide in regulating physiological mechanisms such as vasodilatation, neurotransmission, and modulation of cytokines to protect graft cells and reduce the post-transplant inflammatory environment.
We synthesized Dinitrosyl Iron Complex (DNIC) as a nitric oxide carrier, which can prolong the half-life of nitric oxide in living organisms and increase the transmission distance. By prolonging the time of nitric oxide in the cell, the bioavailability of nitric oxide can be enhanced. The experimental results demonstrated the stability of DNIC in HSFM with/without the addition of 2% FBS and 50 mg/mL BSA, based on which the cellular uptake and intracellular release kinetics of DNIC were evaluated by EPR spectroscopy and NO specific probe (DAF-FM), which showed that the intracellular release mechanism of DNIC provided more stable and efficient nitric oxide delivery. DNIC exhibits a remarkable pro-proliferative effect on CECs and significant antioxidative capacity, as indicated by our in vitro results. Our findings showed that DNIC has the potential to be used for cell protection of donor corneas prior to corneal transplantation, to enhance cell survival in adverse environments, and to promote post-transplant wound healing and reduce the incidence of complications with its anti-inflammatory and antioxidant properties.

目錄
目錄 2
圖目錄 4
表目錄 5
摘要 6
Abstract 7
致謝 8
ㄧ、緒論 9
1-1角膜 9
1-1-1角膜上皮(corneal epithelium) 9
1-1-2前彈力層(Bowman’s Layer) 10
1-1-3角膜基質層 10
1-1-4後彈力層(Descemet’s membrane) 13
1-1-5角膜內皮 13
1-2角膜疾病 15
1-3角膜移植術(keratoplasty) 15
1-3-1全層角膜成形術 (Penetrating keratoplasty, PKP) 16
1-3-2前角膜深層移植術(Deep Anterior lamellar keratoplasty, DALK) 16
1-3-3深板層角膜移植手術(Deep lamellar endothelial keratoplasty, DLEK) 17
1-3-4前角膜深層移植術(Descemet Stripping Automated Endothelial Keratoplasty, DSAEK) 18
1-3-5後彈力層角膜內皮細胞移植術(Descemet Membrane Endothelial Keratoplasty, DMEK) 18
1-4角膜移植排斥 19
1-4-1角膜移植排斥反應的治療 20
2-1ㄧ氧化氮 22
2-1-1ㄧ氧化氮的發展 22
2-1-2ㄧ氧化氮藥物的發展 25
2-1-3一氧化氮供體 27
2-1-3-1有機硝酸鹽(Organic nitrates) 27
2-1-3-2亞硝基硫醇(S-nitrosothiols, RSNOs) 28
2-1-3-3二醇二氮烯(Diazeniumdiolates, NONOate) 29
2-2雙亞硝基鐵錯合物 (DNIC) 30
2-2-1雙亞硝基鐵錯合物的發展 30
二、實驗 33
2-1藥品 33
2-2儀器 35
2-3反應之環境條件 36
2-4緩衝溶液與其他溶液之配製 36
2-4-1 磷酸鹽緩衝生理鹽水(Phosphate-buffer saline, PBS)之配製 36
2-4-2 格里斯試劑Griess reagent solution之配製 36
2-4-3合成[Na-18-crown-6-ether][Fe(CO)3(NO)] 36
2-5小分子化合物合成及製備 37
2-5-1合成[Fe(u-S-thioglycerol)(NO)2]2 (DNIC-COOH) 37
2-6細胞培養 38
2-6-1細胞來源與細胞的生長環境 38
2-6-2細胞解凍活化 38
2-6-3細胞繼代 39
2-6-4細胞存活率試驗(Cell viability test) 39
2-6-5 DNIC進入細胞內的動力學實驗 40
2-6-6 DNIC在細胞內的一氧化氮釋放定量實驗(使用B4G12細胞) 40
2-6-7 DNIC進入細胞內的機制探討實驗 41
2-6-8 免疫螢光染色 42
2-6-9即時定量聚合酶連鎖反應(Quantitative real-time PCR) 42
三、結果與討論 44
3-1 DNIC的合成與鑑定 44
3-2探討DNIC體外之一氧化氮釋放動力學與反應性 45
3-3 DNIC之細胞存活率測試 47
3-4 DNIC進入細胞之動力學探討 49
3-5 DNIC進入細胞之機制探討 52
3-6 使用DNICs可調節HCEC內第一型血紅素氧化酶的表達 55
3-7 DNICs促進HCEC抗氧化能力分析 56
3-7 DNICs維持HCEC之生理功能 58
四、結論 59
4-1結論 59
五、參考文獻 61

圖目錄
Figure 1角膜及眼睛構造 10
Figure 2角膜上皮層構造 11
Figure 3角膜基質內細胞分佈 12
Figure 4角膜基質層結構[11] 13
Figure 5角膜後彈力層層結構[16] 14
Figure 6角膜內皮細胞密度於不同狀況下 15
Figure 7全層角膜成形術 (Penetrating keratoplasty, PKP) 17
Figure 8前角膜深層移植術(Deep Anterior lamellar keratoplasty) 17
Figure 9深板層角膜移植手術(Deep lamellar endothelial keratoplasty) 18
Figure 10前角膜深層移植術(DSAEK) 19
Figure 11後彈力層角膜內皮細胞移植術(DMEK) 20
Figure 12角膜移植排斥 21
Figure 13市面上一氧化氮藥物 27
Figure 14有機硝酸鹽類在體內釋放一氧化氮機制[82] 29
Figure 15常見亞硝基硫醇類藥物 30
Figure 16內源性DNIC的生成[100] 32
Figure 17 DNIC與蛋白質間的交互作用[95] 33
Figure 18 DNIC-COOH之化學結構。 45
Figure 19 DNIC之(a) FT-IR光譜(b) UV-Vis光譜。 46
Figure 20 DNIC在細胞培養液MEM (a)有(b)無添加2% FBS的條件下，隨時間變化的NO累積濃度圖。每個數據點皆為三重複(mean ± SD)。 47
Figure 21 (a) 在細胞培養液HSFM有添加2% FBS的條件下，DNIC的代表性EPR光譜。(b) 在細胞培養液HSFM有(黑)或無(藍)添加2% FBS的條件下，DNIC的代表性EPR光譜。(c) 給予不同時間間隔(0, 0.5, 1, 2, 3, 4, 8 and 24 h)的DNIC-COOH (50 μM)後，在細胞培養液HSFM中protein-bound DNIC生成與瓦解。 48
Figure 22 (a) B4G12細胞給予24 h (b) 48 h不同濃度的DNIC-COOH後的細胞存活率測試。(c) B4G12細胞給予24 h 10-100 μM DNIC-COOH後的細胞存活率測試。(d) B4G12細胞給予24 h (e) 48 h不同濃度的DNIC-COOMe後的細胞存活率測試。 49
Figure 23用(a) (b) DNIC-COOH (75 μM)、(c) (d) DNIC-COOMe (1 μM)處理B4G12細胞的EPR光譜的時間變化 51
Figure 24 (a) DNIC-COOH、(b) DNIC-COOMe在37℃ 處理B4G12細胞時，細胞內protein-bound DNIC生成與瓦解。結果的半衰期皆進一步透過擬一階動力學擬合。每個數據點皆為三重複(mean ± SD)。 51
Figure 25給予0.5 h的DAF-FM (5 μM)、給予6 h的DNIC-COOH (75 μM)及給予0.5 h的DNIC-COOMe (1 μM)所得到的B4G12螢光圖像。 53
Figure 26給予B4G12細胞DAF-FM (5 μM)和DNIC-COOH (75 μM)(藍)、DNIC-COOMe (1 μM) (紅)，分別在不同時間點(0, 1, 2, 4, 6 and 8 h)時細胞的螢光相對強度，兩組結果的半衰期皆進一步透過擬一階動力學擬合。每個數據點皆為三重複(mean ± SD)。 53
Figure 27 用不同類型的抑制劑(a) N-Ethylmaleimide (NEM), (b) Chlorpromazine Hydrochloride (CH), (c) Methyl-beta-cyclodextrin (mβCD), (d) Genistein 的濃度培養三十分鐘B4G12之細胞存活度。*p < 0.05; ***p < 0.005; ****p < 0.0001。 55
Figure 28 B4G12細胞攝入DNICs的吸收機制。用(a) 75 µM DNIC-COOH和(b) 1 µM DNIC-COOMe處理的B4G12細胞的標準化EPR強度顯示NEM的抑製作用，評估白蛋白介導的和硫醇介導的吸收機制的參與。(c) 胞吞作用抑製劑預處理30分鐘後加入75 µM DNIC-COOH共培養6小時，B4G12細胞的標準化EPR強度。每個數據點皆為三重複(mean ± SD)，並以one way ANOVA進行跨組分析，*p < 0.05。 57
Figure 29 B4G12細胞給予DNIC-COOH(75 μM)、DNIC-COOMe(1 μM)後提升HO-1之表現。qPCR的結果顯示了DNICs刺激後HMOX1基因表達隨時間變化之結果。 *p < 0.05; ***p < 0.005。 58
Figure 30 B4G12細胞給予預處理24 h不同濃度的DNIC-COOH(75 μM)、DNIC-COOMe(1 μM)後的氧化性壓力細胞存活率測試。每個數據點皆為六重複(mean ± SD)，並以one way ANOVA進行跨組分析，若P<0.05則為顯著差異。 59
Figure 31 以免疫螢光染色法觀察B4G12與Zonaoccludens-1 (ZO-1)蛋白表現。 60
Figure 32 整體實驗示意圖。 62
表目錄
Table 1統整治療角膜移植排斥方法及使用DNIC在不同預防時間預期發揮的療效 23
Table 2統整DNICs於細胞培養液的半衰期 61

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