全國中小學科展

生物化學

不同種類與濃度的金屬奈米粒子輔佐NaBH4還原對-硝基苯胺反應速率常數的研究

L-多巴在酪氨酸酶的作用下,可以轉換成多巴醌,多巴醌繼而自發轉變為黑色素,在此實驗當中,利用帶有青枯病菌的酪胺酸酶基因片段pBAD-518458-bbr的大腸桿菌(E. coli DH5α)將L-多巴轉換成黑色素,然後將微生物去除,只保留黑色素,以避免之後的實驗受到細菌的干擾。 分別將四種金屬離子,Au3+、Cu2+、Co2+、Pd2+ 以1.0 mM的濃度加入黑色素中,使黑色素將金屬離子還原成金屬奈米粒子,形成含有黑色素與金屬奈米粒子的混合溶液。將黑色素去除,避免之後測吸收時受到干擾。再以冷凍乾燥機抽乾乾燥,去除水分以利保存。 將對-硝基苯胺與已乾燥的金屬依照一定濃度加入96孔盤中,再加入硼氫化鈉當作還原劑,也是提供氫陰離子的來源,將對-硝基苯胺還原成對-苯二胺,用Multi-Mode Microplate Reader (BioTeK)測每隔10秒波長385 nm的吸收,再將數據整理成反應速率常數。在四種金屬當中,奈米金的催化速率最佳,所以選擇金屬金以濃度0.1、0.5、1.0 mM作濃度的探討。

The Characterization of Human Epidermal Stem Cells

The role of Notch signaling in the regulation of growth and differentiation of epithelial stem cells is poorly understood. While specific markers for epidermal stem cells have not yet been identified, members the Notch signaling pathway have been reported to be differentially expressed in the human epidermis. This study sought to demonstrate the presence and distribution of Notch and its ligands, Delta and Jagged, in human keratinocytes, and thereby characterize this subpopulation. Human neonatal foreskin samples were used to obtain isolated epidermal cells. Cells that were shown to be negative for connexin43, a gap junction protein, and positive for keratin14, a basal marker, were classified as presumptive stem cells (PSC). This sorted subpopulation was shown to be small and agranular by flow cytometry analysis. After two weeks in cell culture, PSC revealed a proliferative potential three times greater than non-sorted cells. The PSC exhibited increased expression of Delta and Jagged ligands than the general population. Additionally, RT-PCR confirmed the presence of Jagged and Delta in keratinocytes; however, only Jagged was detected in immunohistochemistry tests. Members of the Notch family were identified by immunohistochemistry in the epithelium and also at the protein- and mRNA-level. The data suggests that variations in the expression of members of the Notch signaling pathway could potentially be used as markers for stem cells of the epithelium; however, further research is necessary to make definitive conclusions, which would provide better insight into Notch regulatory pathways. This understanding could one day allow for the eventual treatment of epithelial damage caused by various skin diseases, injuries, or burns.

利用線蟲模式研究飲食對於神經老化的影響及其分子機制

飲食是否影響老化一直是個有趣的議題。秀麗隱桿線蟲有透明體腔、月餘的生命週期,為研究老化的極佳模式生物,和E. coli OP50相比,Comamonas DA1877會加速線蟲生長並縮短壽命。本研究旨在探討DA1877飲食是否造成線蟲早衰及其分子機制。實驗中先確認DA1877加速線蟲生長,並發現食用此飲食的線蟲具有較嚴重的頭部損害且擺尾速度減緩的老化特徵,說明此飲食使線蟲早衰。也採用Pmec-7::mRFP線蟲比較不同飲食下感覺神經老化狀況,更使用aldicarb藥物探討線蟲的癱瘓速率,發現DA1877不僅使線蟲早衰也改變感覺神經型態與運動神經功能。為了探討此現象的分子機制,採用與氧化壓力相關的核心轉錄因子daf-16 基轉種Pdaf-16:DAF-16a/b::GFP比較不同飲食下細胞核螢光顯現量,得知 DA1877使DAF-16入核表現,推測此飲食對線蟲而言為氧化壓力。已知OP50和DA1877在S-adenosyl methionine (SAM)含量上有顯著差異,未來希望以缺乏SAM合成酶之sams-1突變種進行實驗,了解DA1877使線蟲早衰的路徑。

探討胃幽門螺旋桿菌毒性因子GroES之重要胺基酸組成及其致發炎機制

胃癌為全球癌症致死率第二高的癌症。胃幽門螺旋桿菌(Helicobacter Pylori)為其致癌最重要的因子之一,世界衛生組織更將其歸類於第一群確定性的致癌因子。幽門螺旋桿菌分泌毒性因子GroES蛋白,感染胃上皮細胞後能引起發炎反應;且發炎反應中,以介白素-8(Interleukin 8, IL-8)的釋放量最為顯著。GroES蛋白(全長1-118)在羧基端有28個延伸的胺基酸片段,刪去則GroES蛋白失去誘導細胞釋放IL-8之能力。因此我們希望進一步找出此延伸片段上最關鍵的致發炎片段及機制。 我們每次刪去6個胺基酸,探討GroES蛋白上與致成胃部發炎最為相關的胺基酸片段;接著以加入還原劑、加入螯合劑以及點突變的方式深入分析此致成胃發炎毒性因子的結構,探討可能的致發炎機轉。由實驗結果來看,GroES蛋白羧基端半胱胺酸(cysteine)之間雙硫鍵形成的環狀結構能夠誘導胃上皮細胞釋放IL-8,可能與致胃發炎有關;亦可能是組胺酸(histidine)與鎳離子之間的配位鍵引起細胞的發炎反應。Point mutation結果則顯示cysteine之間雙硫鍵形成的環狀結構。 未來我們將更進一步探討此環狀結構存在的條件,也探討histidine與鎳離子之間的配位鍵對於致發炎的影響。我們希望能將研究成果發展成生物標記分子、疫苗以及單株抗體,進而建立一個應用平台,以儘早發現並治療胃部發炎等胃部疾病。

以蛋白質體學方法鑑定人類肝癌細胞經蕾莎瓦治療之預後的潛力生物標記 Identification of Potential Prognostic Biomarkers in Hepatocellular Carcinoma Cells Treated with Sorafenib

肝癌是死亡率極高的癌症。目前並無非侵入性方法判斷標靶藥物治療效果。蕾莎瓦(Sorafenib)是一種使用於肝癌晚期治療的標靶藥物,但有些病患在治療過程中會出現抗藥性,因此可預測蕾莎瓦治療效果的生物標記相當重要。 血液中的生物標記可及時追蹤疾病進展與預後之評估。本實驗利用質譜法鑑定分析在肝癌細胞(HuH7)中加入蕾莎瓦模擬治療後肝癌的分子機轉,並透過生物資訊軟體了解蛋白質在HuH7細胞中所扮演的角色。我們發現Galectin-3 和HMGB1可能參與腫瘤細胞的增生和遷移,以西方墨點法觀察其表現量,發現Galectin-3 和HMGB1在受到藥物處理後,表現量皆有下降的情形。 蕾莎瓦可抑制B-RAF激酶進而阻斷MAPK pathway。MAPK pathway又可分成ERKs、JNKs和p38/SAPKs三類。為確認Galectin-3之訊息傳遞路徑,將蕾莎瓦和ERK抑制劑處理細胞,發現Galectin-3的表現量隨著時間而下降,證實Galectin-3的表現會受到ERK路徑調控。 Galectin-3與 HMGB1是極具潛力的生物標記可應用於蕾莎瓦的治療,希望這些生物標記可以應用在臨床上。

Novel Biotechnological Approach for Recognition and Purification of Antibody: Lectin Affinity Membranes

Immunoglobulin G is a glycoprotein structured molecule that is produced by the immune system and protects organism from harmful effects of antigens. Ig G amount in the blood plasma is an appropriate indicator of; infection, cancer, diabetes, cardiovascular diseases, Alzheimer and other autoimmune diseases. Besides, purification of Ig G used in the treatment of these diseases from naturel sources is carried out at high costs on the World market. It is hard to obtain Ig G in high amounts and without any decomposes, that’s why it is important to develop new systems that will help to recognize and purify Ig G antibody. In this project, my purpose was; recognizing Ig G antibody with efficient, high amounted, fast, easily, with less toxicity, economically and purifying Ig G in high ratios from its natural sources. For this purpose p(HEMA-EDMA) membranes are synthesized with free radical photo polymerization method and characterized according to SEM images, swelling behaviors FTIR analysis and elemental analysis. In order to adsorb Ig G to polymeric membranes; polymeric membranes are activated with silanization agent (IMEO) and derivatized with Con A which is a lectin affinity ligand. In the SEM results it is examined that membranes are in spherical structures. Highest swelling value is determined as 224.8%.Binding of IMEO was demonstrated with FTIR and Elemental Analysis. Optimum conditions for Ig G adsorption to membranes are; 1.5 mg/ml initial Ig G concentration, 30 minutes of adsorption time, pH 4 citrate buffer 37 0C and without any different ion strength. Optimum adsorption capacity is determined as 253.8 mg/cm2 and it is also determined that this value is 7 times higher than nonspecific Ig G adsorption to p(HEMA-EDMA) membranes. Ig G adsorption-desorption cycles (5 times) proved that product is reusable without losing its adsorption capacity. According to the electrophoresis, Ig G could be desorbed in pure form without any denaturation to its structure.

建立細菌系統的雙分子螢光互補試驗做為α-突觸核蛋白聚集抑制物篩檢平台

帕金森氏症(PD)是一種慢性中樞神經系統退化性疾病,患者臨床症狀包括靜止時震顫、動作遲緩、僵直及黑質緻密部多巴胺神經元的漸進性退化等。PD的主要病理特徵為多巴胺神經元中出現包含α-突觸核蛋白(SNCA)錯誤摺疊、聚集的路易小體。雖然PD的治療方法包括給予左旋多巴或其他藥物、物理治療、手術等,至今尚未有根治的方法。本研究建立雙分子螢光互補試驗與蛋白質摺疊報告者試驗兩種原核細胞平台,作為篩檢可幫助α-突觸核蛋白摺疊的化學伴隨蛋白平台。雙分子螢光互補試驗是將Venus黃螢光蛋白改進版切開成N端(VN1-211)及C端(VC212-239)二段,分別接在SNCA的N端(VN-SNCA)或C端(SNCA-VC),原本沒有螢光的片段可藉融合的SNCA聚集的再組裝而出現螢光。當構築的VN-SNCA and SNCA-VC質體共表現於大腸桿菌後,蛋白質染色及免疫轉漬可偵測到表現的VN-SNCA、SNCA-VC蛋白,並出現伴隨著SNCA聚集所導致的互補螢光。我們以可干擾SNCA聚集的海藻糖來測試此聚集抑制物篩選平台,發現在不影響大腸桿菌生長的狀況下,海藻糖的濃度與螢光下降程度呈正相關,推測因其能減少SNCA聚集,導致螢光分子互補的機率下降。蛋白質報告者試驗是將野生型(WT)與突變型(35/46/61 E-to-K)的α-突觸核蛋白與綠螢光蛋白的融合蛋白(SNCA-GFP)分別表現於大腸桿菌,突變型的α-突觸核蛋白的傾向錯誤摺疊,會影響融合的綠螢光蛋白摺疊,而導致綠螢光下降,而海藻糖的化學伴隨蛋白活性可幫助突變型的α-突觸核蛋白摺疊,因而改善融合的綠螢光蛋白的摺疊,導致綠螢光上升。未來我們用此兩種原核細胞平台,來篩檢可幫助α-突觸核蛋白摺疊的新穎化學伴隨蛋白。

小兵立大功-發現日常生活中可抑制腦癌細胞之植物萃取物

本實驗藉由「篩檢抑制癌細胞增長的藥物」來尋找可以抑制癌細胞生長的植物萃取物。我們希望從日常生活中唾手可得的蔬果類植物中尋得抗癌藥物。曾經在生物課聽老師提過,紫衫中的紫衫醇可抑制乳癌;由此我們產生一個想法:是否從日常生活中的植物中也能找出有效抑制癌症的成份?因此便著手進行。先從尋找相關論文、蒐集植物,經由萃取、篩檢四種蔬果類的不同部位之水粗萃物或酒粗萃物,我們得到三種蔬果類可有效抑制腦癌細胞的增長。之後選出實驗效果較為顯著兩種水粗萃物進行西方墨點法,初步確認影響腦癌細胞生長的可能機轉:Akt以及Erk;實驗過後發現以上有兩種水粗萃物能透過這兩種訊息傳遞分子影響細胞生長。最後再進行高效液相層析法,期望能夠找出抑制腦癌細胞生長的物質。日後希望這部份的實驗能完整,以期最後的成果。

A New Generation Colorimetric Method for Lead Analysis: APTAMER MODIFIED GOLD NANOPARTICLES

Lead is a toxic element which is used in the production of chemicals, dyes, accumulators and various industrial areas. It may cause complications even extended to death when it is taken consistently in high amounts. Lead poisoning is in the first place among the occupational diseases. It is gaining importance to develop new and sensitive methods for lead analysis. Because lead poisoning can progress without any symptoms and poisoning level (10µg/dL) is low. Disadvantages of the systems used for lead analysis are such as longer detection time, being expensive and difficult to implement. The aim of this project is to develop a new generation method in order to detect lead in blood, based on aptamer modified gold nanoparticles. We detected the lead in terms of color change obtained in gold nanoparticle solutions, with composite biochemosensor that is prepared with 20 & 80 nm sized gold nanoparticles and TBA(Thrombin Binding Aptamer). While immobilizing TBA to the gold nanoparticles, we benefitted from the magnificent surface affinity of the –SH (Thiol) groups that modified to the TBA. Gold nanoparticles that are used in development of our biotechnological method do not stimulate the immune system. The preparation of aptamers in completely sterile medium provides us to use our system in the lead detection of blood. Our method can also be used in the lead detection of mediums such as waste water, food and soil. We have developed a biochemosensor that can be used to detect the presence and absence of Pb2+ by taking into consideration the toxic effect in the human body. Also we detected the presence of lead colorimetrically, in low concentration levels and wide interval values of 4.4 – 11 µg/dL. The developed system is first that; it provides TBA to be used with its complimentary sequence detects the presence of lead colorimetrically and can be used in physiological media such as blood. Also our system can detect lead in amounts that are lower than the poisoning threshold.

新穎「螢光素酶—螢光奈米鑽石」細胞化驗機制標記於人類間葉幹細胞之藥物篩選應用與研究

本實驗提出了一個新的細胞化驗平台:結合螢光素酶和螢光奈米鑽石(Luciferase-Fluorescent Nanodiamond;Luc-FND)用來高靈敏檢測極少數量的細胞,克服人體間葉幹細胞(Mesenchymal Stem Cell; MSC)的數量稀少以及來源取得困難的問題。本實驗開發的Luc-FND assay,不同於以往的Luciferase assay,Luc-FND assay利用了FND當奈米載體(約為100nm),將裹上的螢光素酶送入細胞後監測細胞內冷光強度,用以得知細胞胞吞作用的多寡,進一步推算出細胞的存活率。本實驗將此機制應用於被不同濃度的化療用藥阿黴素(Doxorubicin;Dox)處理過的間葉幹細胞。結果顯示Luc-FND assay能夠高靈敏的檢測Dox對於間葉幹細胞的毒性,僅用1 ×103個細胞就能測出低至0.3125M的Dox劑量。本研究結果顯示,Luc-FND複合物是一種高效能的生醫工具,可將生物發光蛋白均質傳遞到間葉幹細胞中,提供了一種檢測和驗證治療成果的新方法。