| Abstract: | 氧化壓力增加造成神經損傷或死亡是許多神經退化性疾病的起因，因此瞭解氧化壓力對神經的毒性及防止氧化壓力誘導神經毒性是目前刻不容緩的研究。已知硫酸鎵 (Gallium sulfate, Ga2(SO4)3) 常被應用在電子工業中，因此作業人員常常會接觸到。硫酸鎵在神經方面仍未有詳細的探討，本研究利用硫酸鎵處理神經細胞 (Neuro 2a，N2a) 觀察對神經的細胞毒性及基因毒性並闡明其路徑。在本研究中結果可分成兩部分，第一部分是氧化壓力所造成的細胞毒性，第二部分是氧化壓力所誘發的抗氧化防禦。首先發現隨著氧化壓力的生成，硫酸鎵會活化 mitogen-activated protein kinases (MAPK) 家族及 p53，p53 藉由調控 B-cell lymphoma 2 (Bcl-2) 家族進而釋放細胞色素 C 及凋亡誘導因子。細胞色素 C 活化半胱胺酸天冬胺酸蛋白酶 (cysteine-aspartic proteases, caspases)-9 及 -3，caspases-9 和 -3 會切割 poly (ADP-ribose) polymerase-1 (PARP-1)。硫酸鎵也會經由 fas receptor (fasR) 及 tumor necrosis factor receptor (TNFR) 活化 caspase-8 並切割 Bid，最終造成 N2a 細胞的 deoxyribonucleic acid (DNA) 損傷及細胞毒性。硫酸鎵生成氧化壓力不僅藉由 nuclear factor erythroid-derived 2-like 2 (Nrf2)，進而導致 heme oxygenase-1 (HO-1) 表現提高，也增加 superoxide dismutase (SOD)、catalase (CAT)、glutathione (GSH) 表現。最後發現，硫酸鎵會經由增加氧化壓力而誘發抗氧化防禦，但是抗氧化能力仍不足以抗衡氧化壓力的程度，因此導致一連串細胞凋亡反應的發生。Recent reports have shown that when oxidative stress occurs in the neuron system, it often results in some neurodegenerative diseases and trigger neuronal loss. Therefore, it’s the top priority to realize oxidative stress that trigger neurotoxicity and prevent neurotoxicity induced by oxidative stress. Ga2(SO4)3 is used extensively in the electronics industry as a component of semiconductors, light emitting diodes, and solar energy applications. So, somepeople would often expose to it. However, the mechanisms of Ga2(SO4)3 in neuron system is still unclear. The purpose of this thesis is to investigate the pathway of Ga2(SO4)3’s cytotoxicity and genotoxicity in neuron cells N2a. In this thesis, the results can be separated into two parts, the first part is realizing oxidative stress that trigger neurotoxicity, the second part is preventing neurotoxicity induced by oxidative stress. First, we demonstrated that Ga2(SO4)3 enhance the phosphorylation of ERK, JNK, p38 and p53 via generation of oxidative stress. The previous invent affect Bcl-2 family which release cytochrome C and AIF. Moreover, cytochrome C activate caspase-9, followed by activating caspase-3 which cleaved PARP-1. Therefore, we further demonstrated that Ga2(SO4)3 induced the activation of caspase-8 which cleaved Bid via death receptor fasR and TNFR. The results have shown that Ga2(SO4)3 induced DNA damage and cytotoxicity in N2a cells. Second, Ga2(SO4)3 induced generation of oxidative stress that not only triggering the ascension of HO-1 expression by activating Nrf2, but also up-regulating the expression of SOD、CAT、GSH. In the summary, Ga2(SO4)3 induced the mechanism of anti-oxidative stress via generation of oxidative stress. But the expression still can not protect the cell from oxidative stress, resulting a series of apoptosis reaction. |
