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研究生： 章陽彬
Zhang, Yang-Bin
論文名稱： 人類肺部上皮細胞受體ACE2應對SARS-CoV-2之舊藥新用研究
Drug Repurposing for ACE2 gene in human lung epithelial cells against SARS-CoV-2
指導教授： 莊淳宇
Chuang, Chun-Yu
口試委員: 陳之碩
Chen, Chi-Shuo
劉耕谷
Liu, Keng-Ku
廖憶純
Liao, Yi-Chun
學位類別： 碩士
Master
系所名稱： 原子科學院 - 生醫工程與環境科學系
Department of Biomedical Engineering and Environmental Sciences
論文出版年： 2023
畢業學年度： 111
語文別： 中文
論文頁數： 112
中文關鍵詞： 嚴重急性呼吸系統綜合征冠狀病毒2 、血管緊張素轉化酶2 、千金藤鹼 、阿奇黴素 、硫酸鋅 、微小核糖核酸
外文關鍵詞： SARS-CoV-2, ACE2, Cepharanthine, Azithromycin, ZnSO4, microRNA
相關次數： 點閱：1  下載：0 
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    • 新型冠狀病毒肺炎(Corona Virus Disease 2019, COVID-19)在2019年爆發盛行於全球，由於造成肺炎和急性呼吸窘迫綜合症(acute respiratory distress syndrome, ARDS)以及急性肝、心和腎損傷等併發症，導致一開始致死率高達5%。嚴重急性呼吸綜合症冠狀病毒2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2)表面刺突蛋白(spike protein)的受體結合區域(receptor binding domain, RBD)，會與宿主細胞上血管緊張素轉化酶2 (angiotensin-converting enzyme 2, ACE2)結合進入細胞。千金藤鹼(Cepharanthine, CEP)為一種天然生物鹼，能抑制非洲綠猴腎Vero E6細胞共培養感染SARS-CoV之病毒活性。有鑒於SARS-CoV與SARS-CoV-2的基因序列具同源性，因此CEP可能是對抗SARS-CoV-2潛在藥物之一。阿奇黴素(Azithromycin, AZT)是臨床常用抗生素，硫酸鋅(ZnSO4)中的鋅離子(Zn+)亦能調節抵抗病毒引起之免疫反應和炎症反應。有研究指出微小核糖核酸(microRNA, miRNA)會通過阻止SARS-CoV-2複製及下調ACE2表達來減少病毒與ACE2結合造成感染。因此，本研究探究CEP、AZT與ZnSO4對於人類肺部細胞藉由miRNA調控改變ACE2表達及其與SARS-CoV-2致病和發炎相關基因表達情形之關聯性。
    本研究發現AZT/ZnSO4處理人類下呼吸道上皮非小細胞肺癌A549細胞及下呼吸道肺腺癌Calu-3細胞後能顯著下降ACE2表達，表示有助於降低SARS-CoV-2病毒透過結合人類肺部細胞ACE2進入宿主體內。雖然CEP不會改變ACE2表達，但CEP與AZT/ZnSO4處理可以顯著增加miR-421-5p與miR-200c-3p表達，顯著降低B0AT1、TMPRSS2、TLR8、IRAK1、NF-κB、AhR及F10表達，表示減少異源二聚體[ACE2：B0AT1]產生並降低SARS-CoV-2刺突蛋白經TMPRSS2切割後與ACE2結合進入體內，減少炎症因子TLR8與IRAK1來降低NF-κB表達，降低肺部黏蛋白表達和凝血因子F10表達，最終減緩肺部症狀。根據以上研究結果推論CEP與AZT/ZnSO4治療能透過調控miRNAs減少ACE2表達進而降低SARS-CoV-2進入體內造成感染，降低TLR8與IRAK1產生以減緩發炎，並且減少黏蛋白表達及血栓形成危害，進而減緩肺部症狀。

    The novel coronavirus disease 2019 (COVID-19) pandemic emerged globally in 2019, leading to severe complications such as pneumonia, acute respiratory distress syndrome (ARDS), acute liver, cardiac, and kidney injuries, initially resulting in a high fatality rate of up to 5%. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) carrying the receptor binding domain (RBD) of the spike protein is capable of entering host cells by binding to angiotensin-converting enzyme 2 (ACE2). Cepharanthine (CEP), a natural alkaloid, has demonstrated the ability to inhibit SARS-CoV viral activity in Vero E6 cells that were co-cultured with SARS-CoV. Regarding the genetic sequence homology between SARS-CoV and SARS-CoV-2, CEP could be a potential agent against SARS-CoV-2. Azithromycin (AZT), a common clinical antibiotic, and zinc ions (Zn+) of ZnSO4 have been implicated in modulating immune and inflammatory responses against viral infections. It has been reported that microRNAs (miRNAs) can reduce viral infection by impeding SARS-CoV-2 replication and downregulating ACE2 expression. Therefore, this study investigated CEP and AZT/ ZnSO4 and their effects on the regulation of ACE2 expression through miRNA in human lung cells, as well as their association with the expression of genes related to SARS-CoV-2 pathogenesis and inflammation.
    This study found that AZT/ZnSO4 significantly reduced ACE2 expression in human lower respiratory tract epithelial non-small cell lung cancer A549 cells and lower respiratory tract lung adenocarcinoma Calu-3 cells. It showed that AZT/ZnSO4 could reduce the entry of SARS-CoV-2 virus into the host body by binding to ACE2 in human lung cells. While CEP did not alter ACE2 expression, treatment with CEP in conjunction with AZT/ZnSO4 significantly increased the expression of miR-421-5p and miR-200c-3p, and markedly decreased the expression of B0AT1, TMPRSS2, TLR8, IRAK1, NF-κB, AhR and F10. These results indicated a decrease in the formation of heterodimers [ACE2:B0AT1] and a diminished TMPRSS2 cleavage, resulting in reduced binding between the SARS-CoV-2 spike protein and ACE2 subsequently for lowering SARS-CoV-2 entry into the host cells. CEP and AZT/ZnSO4 have the potential to reduce the expression of inflammation factors TLR8 and IRAK1 and resulted in a decrease in NF-κB expression, mucin secretion and clotting factor F10 expression, ultimately leading to alleviation of pulmonary symptoms.
    The research findings above suggested that the treatment with CEP and AZT/ZnSO4 potentially regulated miRNAs to reduce ACE2 expression, thereby decreasing the entry of SARS-CoV-2 and its subsequent infection. Additionally, this treatment approach might suppress the production of TLR8 and IRAK1 to mitigate the inflammatory response, mucin secretion and the risk of clot formation. Consequently, the administration of CEP and AZT/ZnSO4 could alleviate pulmonary symptoms.

    摘要………………………………………………………………................................Ⅰ Abstract…………………………………………………………................................Ⅱ 目錄………………………………………………………………………………….Ⅲ 第1章 前言………………………………………………………...............................1 第2章 文獻回顧…………………………………………………...............................2 2.1 新型冠狀病毒肺炎COVID-19…………………………..............................2 2.2 SARS-CoV-2病毒結構………………………………………………………3 2.3 SARS-CoV-2發病機制………………………………………………………4 2.4 血管緊張素轉化酶2……………………………………..............................5 2.5 ACE2與SARS-CoV-2………………………………………………………6 2.6 胺基酸轉運蛋白與SARS-CoV-2………….………….…………………….7 2.7 跨膜絲氨酸蛋白酶2與SARS-CoV-2………………………………………8 2.8 核因子活化B細胞κ輕鏈增強子……...…………………………………...9 2.9 NF-κB與SARS-CoV-2…………………………………..............................10 2.10 凝血因子X與SARS-CoV-2…………………………...............................11 2.11 Toll樣受體8與SARS-CoV-2……………………………………………..12 2.12 微小核糖核酸MicroRNA……………………………..............................14 2.13 miRNA與SARS-CoV-2………………………………...............................15 2.14 miR-421-5p與ACE2………………………………………………………16 2.15 miR-200c-3p與ACE2…………………………………..............................16 2.16 miR-21-5p………………………………………………………………….17 2.17 千金藤堿………………………………………………………………….18 2.18 阿奇黴素………………………………………………………………….18 2.19 硫酸鋅ZnSO4…………………………………………………………….20 第3章 研究目的…………………………………………………………………….21 第4章 材料與方法………………………………………………………………….22 4.1藥物配製……………………………………………………………………22 4.1.1 CEP配製………………………………………………………………….22 4.1.2 AZT配製………………………………………………………………….22 4.1.3 ZnSO4配製………………………………………………………………..22 4.2 細胞培養………………………………………………...............................22 4.3 RNA萃取…………………………………………………………………...23 4.4 反轉錄聚合酶鏈反應…………………...…………………………………23 4.5 定量聚合酶鏈鎖反應定量基因及miRNA表現………………….............24 4.6 A549細胞轉染ACE2質體…………………………………………………26 4.7 Calu-3細胞轉染ACE2質體………………………………………………..26 4.8 A549細胞/Calu-3細胞之ACE2和NF-κB螢光染色……………………...26 4.9 細胞螢光定量分析………………………………………………………...27 4.10 細胞存活率試驗……..…………………………………………………...27 4.10.1 CEP毒性之細胞存活試驗……..……………………………………….27 4.10.2 AZT與ZnSO4毒性之細胞存活試驗……..…………………………….28 4.11 數據統計………………………………………………………………….28 第5章 結果………………………………………………………………………….29 5.1 CEP處理細胞存活之影響…………………………………………………29 5.2 AZT/ZnSO4處理細胞存活之影響………………………….……………...30 5.3 A549細胞處理CEP之目標基因表現……………………………………...31 5.4 Calu-3細胞處理CEP之目標基因表現……………………………………34 5.5 A549細胞處理CEP之miRNA表現………………………………………37 5.6 Calu-3細胞處理CEO之miRNA表現……………………………………..39 5.7 A549細胞處理AZT/ZnSO4之目標基因表現…………………………….41 5.8 Calu-3細胞處理AZT/ZnSO4之目標基因表現…………………………...44 5.9 A549細胞處理AZT/ZnSO4之miRNA表現………………………………47 5.10 Calu-3細胞處理AZT/ZnSO4之miRNA表現…………………………..49 5.11 A549細胞轉染ACE2質體……..…………………………………………51 5.12 Calu-3轉染ACE2質體…………………………………………………....52 5.13 CEP處理對於A549細胞轉染ACE2質體後之目標基因表現…….…..53 5.14 CEP處理對於A549細胞轉染ACE2質體後之蛋白質表現…………….55 5.15 CEP處理對於Calu-3細胞轉染ACE2質體後之目標基因表現………...56 5.16 CEP處理對於Calu-3細胞轉染ACE2質體後之蛋白質表現…………...58 5.17 AZT/ZnSO4處理對於A549細胞轉染ACE2質體後之目標基因表現….59 5.18 AZT/ZnSO4處理對於A549細胞轉染ACE2質體後之蛋白質表現…….61 5.19 AZT/ZnSO4處理對於Calu-3細胞轉染ACE2質體後之目標基因表現...63 5.20 AZT/ZnSO4處理對於Calu-3細胞轉染ACE2質體後之蛋白質表現…...65 第6章 討論………………………………………………………………………….67 6.1 CEP不能改變ACE2但能下降TMPRSS2表達以減少感染SARS-CoV-2風險.......................................................................................................................67 6.2 AZT/ZnSO4減少ACE2與B0AT1表達以降低感染SARS-CoV-2風險...........................................................................................................................68 6.3 AZT/ZnSO4上調miR-200c-3p降低ACE2表達以減少SARS-CoV-2感染………………………………………………………...………………………69 6.4 CEP與AZT/ZnSO4降低發炎基因表現以減緩感染後危害………………………………………………………………………………...70 第7章 結論………………………………………………………………………….74 補充資料……………………………………………………………………………..75 參考文獻……………………………………………………………………………..98 表格目錄 表1 本實驗使用之引子序列……………………………………………...………..25 表2 本研究進行免疫螢光染色實驗之抗體…………………………...…………..27 圖目錄 圖1 全球COVID-19確診人數………………………………………………………2 圖2 SARS-CoV-2結構示意圖………………………………………………………..3 圖3 冠狀病毒基因結構示意圖……………………………………………………...4 圖4 SARS-CoV-2發病機制…………………………………………………………..5 圖5 ACE2在腎素-血管緊張素-醛固酮系統(RAAS)中的作用……………………..6 圖6 ACE/Ang II/AT1受體軸………………………………………………………….7 圖7 B0AT1於SARS-CoV-2感染之作用……………………………………………..8 圖8 TMPRSS2介導ACE2切割……………………………………………………...9 圖9 NF-κB信號蛋白的結構…………………………………………………...……10 圖10 F10在SARS-CoV-2感染中的作用…………………………………………...12 圖11 Toll樣受體信號通路…………………………………………………………..13 圖12 miRNA生成與作用機制………………………………………………………14 圖13 CEP結構圖…………………………………………………………………….18 圖14 AZT結構圖…………………………………………………………………….20 圖15 CEP處理A549細胞與Calu-3細胞之細胞存活情形………………………...29 圖16 AZT/ZnSO4處理A549細胞與Calu-3細胞之細胞存活情形………………..30 圖17 A549細胞處理CEP之基因表現……………………………………………...33 圖18 Calu-3細胞處理CEP之基因表現…………………………………………….36 圖19 A549細胞處理CEP之miRNA表現………………………………………….38 圖20 Calu-3細胞處理CEP之miRNA表現………………………………………...40 圖21 A549細胞處理AZT/ZnSO4之基因表現……………………………………...43 圖22 Calu-3細胞處理AZT/ZnSO4之基因表現…………………………………….46 圖23 A549細胞處理AZT/ZnSO4之miRNA表現………………………………….48 圖24 Calu-3細胞處理AZT/ZnSO4之miRNA表現………………………………...50 圖25 A549細胞進行不同濃度ACE2質體轉染……………………………………51 圖26 Calu-3細胞進行不同濃度ACE2質體轉染…………………………………..52 圖27 A549細胞轉染ACE2質體後處理CEP之基因表現…………………………54 圖28 A549細胞轉染ACE2質體後處理CEP之蛋白質表現………………………55 圖29 Calu-3細胞轉染ACE2質體後處理CEP之基因表現………………………..57 圖30 Calu-3細胞轉染ACE2質體後處理CEP之蛋白質表現……………………..58 圖31 A549細胞轉染ACE2質體後處理AZT/ZnSO4之基因表現…………………60 圖32 A549細胞轉染ACE2質體後處理AZT/ZnSO4之蛋白質表現………………62 圖33 Calu-3細胞轉染ACE2質體後處理AZT/ZnSO4之基因表現………………..64 圖34 Calu-3細胞轉染ACE2質體後處理AZT/ZnSO4之蛋白質表現……………..66 圖35 CEP減少人肺上皮細胞SARS-CoV-2感染與致病相關基因以預防感染減緩感染症狀………………………………………………………………………72 圖36 AZT/ZnSO4減少人肺上皮細胞SARS-CoV-2感染與致病相關基因以預防感染減緩感染症狀………………………………………………………………73 補充資料：表格目錄 表S1 A549細胞處理CEP之基因表現量改變之倍數……………………………...75 表S2 A549細胞處理CEP之基因相對表現量……………………………………...76 表S3 Calu-3細胞處理CEP之基因表現量改變之倍數…………………………….77 表S4 Calu-3細胞處理CEP之基因相對表現量…………………………………….78 表S5 A549細胞處理AZT/ZnSO4之基因表現量改變之倍數……………………...79 表S6 A549細胞處理AZT/ZnSO4之基因相對表現量……………………………...80 表S7 Calu-3細胞處理AZT/ZnSO4之基因表現量改變之倍數……………………81 表S8 Calu-3細胞處理AZT/ZnSO4之基因相對表現量……………………………82 表S9 A549細胞轉染ACE2質體之基因表現量改變之倍數………………………83 表S10 A549細胞轉染ACE2質體之基因相對表現量……………………………..83 表S11 Calu-3細胞轉染ACE2質體之基因表現量改變之倍數……………………84 表S12 Calu-3細胞轉染ACE2質體之基因相對表現量……………………………84 表13 A549細胞轉染2.5 ng ACE2質體處理CEP之基因表現量改變之倍數……..85 表14 A549細胞轉染2.5 ng ACE2質體處理CEP之基因相對表現量……………..86 表15 Calu-3細胞轉染5 ng ACE2質體處理CEP之基因表現量改變之倍數……...87 表16 Calu-3細胞轉染5 ng ACE2質體處理CEP之基因相對表現量……………...88 表17 A549細胞轉染2.5 ng ACE2質體處理AZT/ZnSO4之基因表現量改變之倍數………………………………..……………………………………………..89 表18 A549細胞轉染2.5 ng ACE2質體處理AZT/ZnSO4之基因相對表現量……..90 表19 Calu-3細胞轉染5 ng ACE2質體處理AZT/ZnSO4之基因表現量改變之倍數…………………………………..………………………..…………………91 表20 Calu-3細胞轉染5 ng ACE2質體處理AZT/ZnSO4之基因相對表現量……..92 表21 A549細胞轉染ACE2質體後處理CEP之ACE2/NF-κB螢光染色強度(40X)…………………………………..………………………………………93 表22 Calu-3細胞轉染ACE2質體後處理CEP之ACE2/NF-κB螢光染色強度(40X)……………………………..……………………………………………93 表23 A549細胞轉染ACE2質體後處理AZT/ZnSO4之ACE2/NF-κB螢光染色強度(40X)…………………………..……………………………………………93 表24 Calu-3細胞轉染ACE2質體後處理AZT/ZnSO4之ACE2/NF-κB螢光染色強度(40X)..………………………………………………………………………94 補充資料：圖目錄 圖S1 A549細胞處理CEP之細胞毒性試驗……………………….………………..95 圖S2 Calu-3細胞處理CEP之細胞毒性試驗……………………………………….95 圖S3 A549細胞處理AZT/ZnSO4之細胞毒性試驗…………...……………………96 圖S4 Calu-3細胞處理AZT/ZnSO4之細胞毒性試驗………………………………96 圖S5 A549/Calu-3細胞之ACE2/NF-κB表現之免疫螢光染色特寫圖……………97

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