臺灣博碩士論文加值系統

棘冠海星 (Acanthaster planci) 又稱魔鬼海星，分類為棘皮動物門，海星綱，瓣棘海星目，長棘海星科。以珊瑚為食，大量出現會破壞珊瑚礁生態，體表佈滿棘刺可分泌黏液和毒液，且包含多種生物活性如：溶血活性、動物致死性、水腫形成、磷脂酶 A2 活性、血管通透性增加和巨噬細胞釋放組織胺等活性。本研究以 2010 年開始在臺灣澎湖大量出現的棘冠海星為樣品，進行其棘刺毒液之生物活性與毒性分析。
研究中將棘冠海星分為不同部位，包括棘刺、體壁、幽門盲囊和生殖腺，以 phosphate buffer saline (PBS) 緩衝溶液進行水溶性物質萃取，並進行生物活性分析，結果顯示海星的棘刺萃取物具有較佳的生物活性，尤其以細胞毒殺性最為顯著。棘刺水溶性萃取物可以視為棘刺毒液萃取物 (A. palnci spine venom, ASV)，對於溶血活性具有顯著的劑量依賴性，溶血活性的最適 pH 值環境約為 7.0~7.4，在 pH 低於 3.0 或高於 8.0 的環境下，其溶血活性會明顯地降低。棘刺毒液以 10 mM 銅離子處理，或者將棘刺毒液加熱至 100℃ 作用 60 分鐘，皆可以使溶血活性完全喪失。棘刺毒液對於多種細胞皆具有顯著的毒殺性，其中對於人類黑色素瘤細胞 A375.S2 的效果最為顯著。棘刺毒液在 40℃ 的環境下其細胞毒殺性依然顯著，然而加熱至 80℃ 之後其細胞毒殺性便會劇烈的降低。棘刺毒液必須在 pH 小於 2.0 或大於 12.0 的環境下，細胞毒殺性才會有明顯的喪失。棘刺毒液以銅離子與抗氧化劑 N-acetylcysteine (NAC) 進行處理，也會造成細胞毒殺性降低。
為了探討棘冠海星棘刺中抗腫瘤活性的毒素，利用快速蛋白質層析 (fast protein liquid chromatography, FPLC) 從棘冠海星棘刺毒液中純化出具有細胞毒殺性的毒素 (cytotoxic toxin of A. planci venom, CAV)，並經由電噴灑質譜儀分析 (electrospray ionization- mass spectrometry, ESI-MS) 的方式，鑑定出純化出的毒素為 plancitoxin I。ASV 和 CAV 對於多種腫瘤細胞具有細胞毒殺性，之後以 A375.S2 做為模式細胞，分析細胞毒殺性的相關機制。結果顯示 ASV 和 CAV 會造成細胞乳酸脫氫酶 (lactate dehydrogenase, LDH) 釋放量增加，並且具有濃度依賴性。在細胞凋亡相關試驗中，顯示 ASV 和 CAV 也會造成細胞內活性氧物質 (reactive oxygen species, ROS) 含量增加以及粒線體膜電位 (mitochondrial membrane potential, ΔΨm) 降低，並會使核內 DNA 裂解成 100~200 bp 的片段。
接著欲探討 CAV 造成 A375.S2 細胞的氧化壓力和內質網壓力相關的相關分子機制，結果顯示 CAV 會造成細胞內的抗氧化酵素超氧化物歧化酶 (superoxide dismutase, SOD) 和過氧化氫酶 (catalase, CAT) 活性降低，也會造成總硫醇類物質和粒線體 DNA 的強度降低，並促使脂質過氧化的增加。在內質網壓力相關實驗中，CAV 會增加細胞內鈣離子的釋放量，並使內質網相關的伴護蛋白 GRP78 和促進凋亡蛋白 CHOP 的蛋白質表現量上升。CAV 也會使細胞內的凋亡蛋白酶如 caspase-3、caspase -8 和 caspase -9 的活性增加，以及降低 Bcl-2 家族蛋白 Bcl-2/Bax 的比率，而促進細胞凋亡的發生。
海星體內的皂素稱為海星皂素 (asterosaponin)，為海星體內主要的二次代謝物質，也是主要的生理活性物質，在科學家的研究下發現，具有溶血、抗癌、抗病毒和抗菌的能力。海星皂素容易藉由水、甲醇或乙醇提取出，因此本研究，乃萃取棘冠海星之乙醇萃取物 (ethanol fraction, EF)，並以有機溶劑進行液相分離，結果顯示，以正丁醇層 (butanol fraction, BF) 的皂素含量最高，因此 BF 可以代表海星皂素萃取物。在生物活性分析中，乙醇萃取物具有一定程度的抗氧化能力，包括 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)(ABTS) 和 2,2-diphenyl-1-picrylhydrazyl (DPPH) 自由基的清除力，螯合亞鐵能力以及還原能力，其中以乙醇萃取物具有最佳之抗氧化能力。細胞毒殺性實驗結果顯示，棘冠海星皂素萃取物對於人類黑色素瘤細胞 A375.S2 具有細胞毒殺性，其作用機制為引起細胞中 ROS 上升以及粒線體膜電位下降，之後造成 caspase-3 活性上升引起細胞凋亡，甚至細胞壞死發生。
有鑑於探討海星生物活性物質的動物實驗較少，本研究乃以棘冠海星皂素萃取物 (BF) 進行動物餵食毒性實驗。以 ICR 雄性小鼠。為實驗動物之急毒性實驗中，發現餵食 BF 對於小鼠的半致死劑量 LD50 約為 520.34 mg/kg。在亞急毒性實驗中，小鼠以 BF 管灌連續餵食 28 天，其紅血球、血紅素和血球容積比皆有顯著增加，此外 BF 也會造成小鼠溶血現象。在肝臟毒性分析中，BF 會降低小鼠血漿及肝臟中的抗氧化物質 SOD、CAT；與總硫醇的含量會降低，並造成脂質過氧化升高，使小鼠受到氧化壓力的傷害。在組織病理切片的觀察中，餵食高劑量 BF 之小鼠其肝臟有受損的現象。棘冠海星之二次代謝物雖然具有許多生物活性，然而其中之皂素卻具有毒性，在應用上必須慎重。

The crown-of-thorns starfish (Acanthaster planci) is the venomous starfish as well as a destroyer of coral reefs. The crown-of-thorns starfish A. planci destroys coral reefs and has been involved in significant events, such as the crown-of-thorns starfish abnormal outbreaks. The back of A. planci is covered with many sharp spines. Previous studies showed that the crude toxin extracted from the spines exhibits the following diverse biological activities: mouse lethality, hemolytic activity, capillary permeability increasing activity, edema-forming activity, phospholipase A2 (PLA2) activity and histamine releasing activity from mast cells.
In this study, the active substance extracts were done with PBS buffer. To assay the cytotoxic, hemolytic, and antioxidant properties of the water soluble extract from spine, body wall, pyloric cecum, and gonad of A. planci. Relative to other parts extract, the spine extract possessed the most biological activity, especially in cytotoxic activity. A. planci spine venom (ASV) caused hemolysis and cytotoxicity at a dose-dependent significantly. The highest activity of ASV was measured at pH 7.0-7.4; ASV-dependent hemolysis was sharply reduced when the pH was lower than 3.0 or greater than 8.0. There was almost no hemolytic activity when the concentration of Cu2+ was increased to 10 mM. Furthermore, incubation at 100 °C for 60 min sharply decreased the hemolytic activity of ASV. The cytotoxicity of ASV to human melanoma cell A375.S2 was relatively well retained at temperature less than 40°C, and sharply lost at temperature more than 80°C. The cytotoxicity of ASV also sharply lost at extreme pH environments (pH was lower than 2.0 and higher than 12.0). The cytotoxicity of ASV was attenuated when treated with Cu2+ and anti-oxidant N-acetylcysteine.
In order to understand the antitumor activity of toxin from A. planci in Penghu, Taiwan, the cytotoxic toxin of A. planci venom (CAV) was purified by fast protein liquid chromatography (FPLC) and identified as plancitoxin I. The results indicated that cells after incubating with A. planci spine venom (ASV) and purified toxin (CAV) significantly decreased cell viability and lactate dehydrogenase (LDH) level in a concentration-dependent manner was increased. The assays indicated that purified toxin promoted reactive oxygen species (ROS) productions, loss of mitochondrial membrane potential (ΔΨm), and inter-nucleosomal DNA fragmentation in A375.S2 cells. Following, the study was investigated the molecular mechanism underlying the cytotoxicity function of palncitoxin I by focusing on the oxidative stress, mitochondrial dysfunction and endoplasmic reticulum (ER) stress pathway in human melanoma A375.S2 cells. The CAV was found to reduce the cellular antioxidant enzymes such as SOD and CAT, and there was significantly decreased in total thiols level and mtDNA integrity, and enhanced the lipid peroxidation. In addition, CAV increased cytosolic Ca2+ concentration, and enhanced the expression of the ER molecular chaperones GRP78 and CHOP in a dose-dependent manner. CAV significantly elevated the activity of caspase-3, -8 and -9, and reduced the ratio of Bcl-2/Bax. The results demonstrated that plancitoxin I inhibits the proliferation of A375.S2 cells through induction of oxidative stress, mitochondrial dysfunction and ER stress associated apoptosis.
Many studies currently researching marine invertebrates to determine the therapeutic potential of their bioactive materials have been showing very promising results. Starfish possesses many useful pharmacological and biological characteristics. In this study, A. planci was extracted with 70% ethanol and lyophilized to obtain an ethanol fraction. The ethanol fraction was dissolved with water and defatted with petroleum ether to obtain a non-polar fraction. The residual solution was successively partitioned with ethylacetate and butanol to obtain an ethylacetate fraction and butanol fraction, respectively. Four fractions were used to examine the antioxidant and anticancer properties. The ethanol fraction of A. planci contained the highest antioxidant effects such as ABTS, DPPH, Fe2+ chelating activity and reducing power when compared with four fractions. Among the four fractions, the butanol fraction was especially shown to inhibit human malignant melanoma A375.S2 cells’ proliferation, which is involved in the apoptotic progression. This fraction could induce apoptosis and even necrosis in A375.S2 cells as evidenced by double staining with an annexin V-FITC and PI assay and DNA fragmentation analysis. These results indicated that the starfish A. planci is a good resource for obtaining the biologically active substances for antioxidant and anticancer effects.
However, there was little toxicological information of asterosaponins. The study evaluated potential toxicity of the asterosaponins and analyzed the oxidative stress harm in mice. The present work evaluated the toxicity of the butanol fraction (BF) of crown-of-thorns starfish (Acanthaster planci) in ICR mice, and the BF was used as the asterosaponins extract sample. In acute toxicity assay, the LD50 of the BF is about 520.34 mg/kg body weight. In sub-acute toxicity test for 28 days, the BF significantly increases in hematological parameters, including red blood cell, hemoglobin, hematocrit and mean corpuscular hemoglobin concentration, it also causes hemolytic activities. The BF induces the hepatotoxic injury through induction of oxidative stress by elevating the lipid peroxidation and decreasing the antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and total thiols. Based on microscopic observations, the BF showed harmful effect on the histomorphology change of liver. Thus, the bioactive secondary metabolites in the BF of A. planci induce a harmful effect in ICR mice.

Publication of Dissertation I
摘要 IV
Abstract VI
目次 IX
圖次 XIII
表次 XX
Glossary of Abbreviation XXI
壹、研究背景 1
一、海洋生物刺毒介紹 2
(一) 海洋生物刺毒蛋白 2
(二) 常見具刺毒之海洋生物介紹 2
(三) 海洋生物毒素之生理活性利用 5
二、棘冠海星介紹 6
(一) 棘冠海星生態習性 6
(二) 棘冠海星刺傷案例 7
三、棘冠海星主要毒素介紹 8
四、棘冠海星毒液之生物活性 11
五、海洋生物天然物介紹 13
(一) 海洋生物天然物藥用介紹 13
(二) 海洋天然物的結構鑑定 13
六、海星皂素介紹 15
(一) 皂素結構特性 15
(二) 海星皂素之生物活性 16
(三) 海星皂素萃取與分離 17
貳、研究內容 18
第一章 棘冠海星水萃取物之生物活性與刺毒安定性探討 19
一、前言 19
二、材料方法 20
(一) 樣品採集 20
(二) 棘冠海星水溶性物質萃取 20
(三) 蛋白質含量測定 20
(四) 蛋白質電泳分析 20
(五) PLA2 活性測定 22
(六) 抗氧化實驗 22
(七) 溶血活性分析 23
(八) 細胞毒殺性分析 24
(九) 棘冠海星棘刺水萃物安定性測定 25
(十) 統計分析 25
三、結果 26
(一) 棘冠海星各部位水溶性萃取物之蛋白質與PLA2 分析 26
(二) 棘冠海星各部位水溶性萃取物之抗氧化能力分析 26
(三) 棘冠海星棘刺毒液萃取物 (ASV) 之溶血活性 26
(四) 不同離子濃度對 ASV 溶血活性之影響 27
(五) 不同 pH 值對 ASV 溶血活性之影響 27
(六) 不同加熱時間對 ASV 溶血活性之影響 27
(七) 棘冠海星棘刺毒液萃取物 (ASV) 之細胞毒殺性 27
(八) 不同加熱時間對 ASV 細胞毒殺性之影響 28
(九) 不同 pH 對 ASV 細胞毒殺性之影響 28
(十) 銅離子對 ASV 細胞毒殺性之影響 28
(十一) NAC 對 ASV 細胞毒殺性之影響 28
四、討論 29
第二章 純化之棘冠海星毒素對黑色素瘤細胞 A375.S2 抑制能力之探討 49
一、前言 49
二、材料方法 51
(一) 樣品採集 51
(二) 棘冠海星毒素之純化 51
(三) 棘冠海星毒素之膠體電泳分析 51
(四) 蛋白質鑑定 51
(五) 腫瘤細胞毒殺與細胞凋亡分析 52
(六) 統計分析 54
三、結果 55
(一) 棘冠海星棘刺毒液萃取物之細胞凋亡探討 55
(二) 棘冠海星毒素 plancitoxin I 之純化 56
(三) 棘冠海星毒素 plancitoxin I 之細胞毒殺性 56
(四) 棘冠海星毒素 plancitoxin I 之細胞凋亡探討 56
四、討論 58
第三章 棘冠海星毒素 Plancitoxin I 引起人類黑色素瘤細胞 A375.S2 氧化壓力與內質網壓力之探討 79
一、前言 79
二、實驗方法 80
(一) 樣品採集 80
(二) 棘冠海星毒素之純化 80
(三) 細胞氧化壓力分析 80
(四) 細胞內質網壓力與細胞凋亡因子分析 82
(五) 統計分析 83
三、結果 84
(一) 細胞內氧化壓力分析 84
(二) 細胞內質網壓力分析 84
(三) 細胞凋亡相關分子分析 85
四、討論 86
第四章 棘冠海星皂素萃取物之生物活性探討 97
一、前言 97
二、實驗方法 98
(一) 樣品採集 98
(二) 固醇類醣苷與海星皂素萃取 98
(三) 總皂素含量測定 98
(四) 總多酚含量測定 98
(五) 抗氧化能力 98
(六) 腫瘤細胞生長抑制性分析 98
(七) 細胞凋亡分析 98
(八) 統計分析 99
三、結果 100
(一) 固醇類醣苷及海星皂素之萃取 100
(二) 總皂素含量測定 100
(三) 抗氧化實驗 100
(四) 溶血活性分析 101
(五) 腫瘤細胞毒殺性分析 101
(六) 正丁醇層萃取物對於 A375.S2 細胞凋亡特性分析 101
四、討論 103
第五章 棘冠海星皂素萃取物對 ICR 小鼠之毒性分析 118
一、前言 118
二、實驗方法 119
(一) 樣品採集 119
(二) 海星皂素萃取 119
(三) 動物毒性試驗 119
(四) 統計分析 122
三、結果 123
(一) 小鼠急毒性試驗 123
(二) 小鼠亞急毒性試驗 123
四、討論 125
參、綜合結果與討論 138
參考文獻 139
謝辭 155

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