臺灣博碩士論文加值系統

在美國，每年有 750,000 件中風新案例出現，並且排名位居前十大死因第三名。缺血型中風占中風發生率 70%，而缺血型中風主要是因為血液供應減少，無法運輸氧氣和養分，進而造成神經功能缺損。牛樟芝為台灣最著名之傳統偏方，但目前很少人將牛樟芝探討其神經保護機制，因此本研究目的在於評估牛樟芝酒精萃取物在體外試驗部分是否可防止 H2O2 及 CoCl2 誘導下之氧化壓力傷害，並防止體內試驗在缺血再灌注下誘導之腦損傷。結果顯示，牛樟芝酒精萃取物具有清除自由基之能力，並可抑制 PC12 類神經細胞及 C6 膠質瘤細胞受到 H2O2 及 CoCl2 誘導下之脂質過氧化及活性物質 ROS 之生成，進而增加細胞存活率。以牛樟芝酒精萃取物 (385、770、1540 mg/kg) 管餵 SD 大鼠三週後可改善中大腦動脈梗塞手術 (MCAO) 所引起之 Nrf2 及 HO-1 mRNA 表現，下調發炎因子 TNF-α、iNOS 和 COX-2，增加缺氧誘導因子 HIF-1α 表現，並恢復缺血再灌注下之抗氧化酵素 GPx、CAT及 SOD 活性。此外，在缺血再灌注後其脂質過氧化表現隨著牛樟芝酒精萃取物劑量的提升呈現劑量依賴性地減少。因此本研究猜測牛樟芝酒精萃取物可預防缺血性中風是藉由抗氧化及抗發炎機制達到有效的神經保護作用。

Stroke is a common disease, and it is estimated that 750,000 new strokes occur annually in the U.S. and also is the third leading cause of death. Ischemia strokes accounted for the majority of stroke cases (70%), it occurs when the blood supply is diminished resulting in either a transient ischemic attack or a more long lasting neurological deficit due to an infarction in the brain. Antrodia camphorata (A. camphorata) is well-known in Taiwan as a traditional medicine. However, little is known about its neuroprotective mechanism. The purpose of this study was to evaluate the ability of A. camphorata alcohol extracts (AC-AE) to protect against H2O2 and CoCl2-induced oxidative stress in vitro, and use ischemia/reperfusion-induced brain injury in vivo. AC-AE scavenged the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH). It also decrease lipid peroxidation and reactive oxygen species (ROS) in C6 and PC12 cell with IC50 value about H2O2 and CoCl2 , and increase cell survival. AC-AE dose (385、770、1540 mg/kg per day, p.o., 4 week) ameliorated the increase mRNA expression of Nrf2 and HO-1, downregulated inflammatory cytokine mRNA expression (TNF-α), incresed hypoxia inducible factor (HIF-1α) levels, restored the decrement in the glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) activitiy of serum and brain tissue caused by ischemia/reperfusion (I/R) in SD rat. Furthermore, it also dose-dependently inhibited the formation of lipid peroxidative products after I/R. These results suggest that AC-AE exerts effective prevention ischemia steoke against oxidative stress and hypoxia by mediating anti-oxidative, anti-inflammatory and neuroprotective mechanism.

謝誌 I
摘要 II
Abstract III
目次 VI
圖表目次 VIII
名詞縮寫 IX
壹、 緒論 1
貳、 文獻回顧 2
一、 腦血管疾病概述 2
(一)、 腦血管疾病現況 2
(二)、 現今通用治療方法 2
(三)、 缺血性腦中風成因 2
(四)、 自由基對腦部之損傷 3
(五)、 自由基對腦缺血性中風之損害途徑 4
(六)、 Nrf2/ARE抗氧化防禦訊息傳導對於中風的神經保護作用 5
(七)、 缺血下 HIF-1α 對神經之保護作用 6
二、 牛樟芝之介紹 7
(一)、 牛樟芝簡介 7
1. 牛樟芝學名之命名與分類 7
2. 牛樟芝型態 8
3. 牛樟芝培養法 8
(二)、 牛樟芝成分與生理活性 8
(三)、 安全性及毒性研究 9
(四)、 抗氧化功能之相關研究 9
(五)、 抗發炎功能之相關研究 10
(六)、 抑制腫瘤生長研究 10
(七)、 護肝功能之相關研究 10
(八)、 提升免疫力及調節免疫功能之研究 10
(九)、 保護神經之研究 11
參、 整體實驗設計 12
一、 細胞模式及流程 12
二、 動物分組及流程 13
肆、 實驗材料及方法 14
一、 材料 14
(一)、 牛樟芝來源 14
(二)、 動物來源 14
(三)、 細胞來源 14
(四)、 實驗藥品 14
(五)、 儀器設備 16
二、 方法 17
(一)、 牛樟芝酒精萃取物抗氧化分析 17
1. DPPH自由基清除能力 17
2. 還原力測定 18
(二)、 細胞模式 18
1. 細胞株解凍 18
2. 細胞株培養 18
3. 以過氧化氫 (H2O2) 誘導細胞氧化損傷 19
4. 低氧模擬劑 (CoCl2) 模擬腦部缺氧環境 19
5. 細胞存活率試驗 (MTT assay) 19
6. 脂質過氧化 (MDA) 測定 20
7. 利用流式細胞儀分析細胞內ROS含量 20
(三)、 動物模式 21
1. 動物飼養分組與樣品處理 21
2. 實驗動物分組 21
3. 中大腦動脈缺血與再灌流 (ischemia-reperfusion) 模式 22
4. 動物犧牲、採血和腦部摘取 22
5. 腦切片梗塞面積 (TTC) 染色分析 23
6. 超氧化物歧化酶 (Superoxide dismutase, SOD) 活性測定 23
7. 過氧化氫分解酶 (Catalase, CAT) 活性測定 23
8. 麩胱苷肽過氧化酶 (Glutathion peroxidase, GPx) 活性測定 24
9. ELISA分析血漿中細胞激素含量 24
10. Immunoblot分析腦萃取液中HIF-1α 蛋白質表現 25
11. 利用RT-PCR分析iNOS, COX-2, Nrf2, HO-1基因表現 27
(四)、 統計方法 29
伍、 結果與討論 30
(一)、 牛樟芝酒精萃取物其抗氧化能力分析 30
1. DPPH 自由基清除能力 30
2. 氧化還原能力 30
(二)、 牛樟芝酒精萃取物在氧化及低氧損傷下對神經細胞保護作用 30
1. 牛樟芝酒精萃取物對於細胞存活率之影響 30
2. 牛樟芝酒精萃取物對H2O2 及 CoCl2 誘導氧化及低氧損傷下其細胞
存活率之影響 31
3. 牛樟芝酒精萃取物對 H2O2誘導氧化壓力下 ROS 生成之影響 31
4. 牛樟芝酒精萃取物對CoCl2 誘導低氧損傷下 ROS 生成之影響 32
5. 牛樟芝酒精萃取物對 H2O2 和 CoCl2 誘導氧化及低氧損傷下造成脂
質過氧化之影響 32
(三)、 牛樟芝酒精萃取物對缺血性中風大鼠之影響 33
1. 牛樟芝酒精萃取物對中風體積之影響 33
2. 牛樟芝酒精萃取物對促發炎因子 (TNF-α) 表現之影響 33
3. 牛樟芝酒精萃取物對內生性抗氧化酵素之影響 33
4. 牛樟芝酒精萃取物對缺血性中風大鼠脂質過氧化作用之影響 34
5. 牛樟芝酒精萃取物對發炎因子 (iNOS、COX-2) 基因表現之影響 34
6. 牛樟芝酒精萃取物對內生性抗氧化反應基因 (Nrf2、HO-1) 表現之影
響 35
7. 牛樟芝酒精萃取物對缺氧誘導因子 (HIF-1α) 蛋白表現之影響 35
陸、 結論 36
參考文獻 37
圖表 49
附錄 70

王升陽 (2010)。你所不知道的牛樟芝。蘋果屋出版社。台北。台灣。
王伯徹、陳啟楨、華傑 (1998)。食藥用菇類的培養與應用，食品工業發展研究所，第144-150頁。台北。台灣。
王雅欣 (2008)。樟芝抗發炎活性成分及其研究。中興大學農藝學系所碩士論文。台中。台灣。
台灣腦中風學會 (2012)。靜脈血栓溶解劑治療急性缺血性腦中風之一般準
則。台北。台灣。
行政院衛生署 (2012)。民國100年國人十大死因統計。台北。台灣。
江素英、吳焜裕、王秋萍、魏逸傑、施睿宏、高尚德、謝慶良 (2002) 。樟芝之致基因毒性與抗基因毒性評估，台灣保健食品協會第二屆第二次年會大會議程及論文摘要，第48頁。台北。台灣。
李一宏 (2003)。樟芝菌絲體之培養及其多醣體抗乙型肝炎病毒活性評估。私立中國醫藥學院中國藥學研究所碩士論文。台中，台灣。
沈立言 (2000)。牛樟芝菌絲體發酵萃取液對肝臟生理機能性之影響，89年度保健食品研究開發計畫心得發表會。台北。台灣。
林家樑 (1989)。膽固醇是腦血管疾病的元兇。亞洲醫藥網健康生活家。台北。台灣。
陳秀雯，陳清農，黃仕政，許勝傑，曹虹萍，洪鳴遠，傅麒玲，陳勁初 (2002)。
樟芝菌絲體之免疫調節功能評估。第 326 頁。中華民國食品科學技術學會第三十二次學員大會手冊。
陳勁初、林文鑫、陳清農、許勝傑、黃仕政、陳炎鍊 (2001)。台灣特有真菌-樟芝菌絲體之開發，第7-22頁。台北。台灣。
陳政憲 (1996)。樟芝清除香菸萃取液之自由基及抑制平滑肌細胞氧化傷害。朝陽科技大學應用化學系碩士論文。台北。台灣。
黃鈴娟 (2000)。樟芝與姬松茸之抗氧化性質及其多醣組成分析。中興大學食品科學研究所碩士論文。台中。台灣。
黃元辰 (2011)。 牛樟芝萃取物中與兩性黴素協同抗癌成分之探討。臺北醫學大學醫學科學研究所學位論文。台北。台灣。
楊燿銘 (2010)。生技時代的皿培式牛樟芝。巨煒出版。台北，台灣。
陳怡穎 (2003)。台灣土肉桂葉精油脂組成與抗氧化性。國立台灣大學食品科技研究所碩士論文。台北。台灣。
蔡宜殷 (1991)。以Melatonin治療暫時性局部腦缺血白鼠有助其電生理及神經行為之改善。國立成功大學醫學工程研究所碩士論文。台南。台灣。
The top 10 causes of death, 2011. Word Health Organization.
http://www.who.int/mediacentre/factsheets/fs310/en/index.htmL data downloaded in 11/25/2011.
Abraham, N. G., Asija, A., Drummond, G., &; Peterson, S. (2007). Heme oxygenase -1 gene therapy: recent advances and therapeutic applications. Curr Gene Ther, 7(2), 89-108.
Abraham, N. G., &; Kappas, A. (2005). Heme oxygenase and the cardiovascular-renal system. Free Radic Biol Med, 39(1), 1-25.
Akyol, O., Herken, H., Uz, E., Fadillioglu, E., Unal, S., Sogut, S., Ozyurt, H., &; Savas, H. A. (2002). The indices of endogenous oxidative and antioxidative processes in plasma from schizophrenic patients. The possible role of oxidant/antioxidant imbalance. Prog Neuropsychopharmacol Biol Psychiatry, 26(5), 995-1005.
Anderson, D., &; Phillips, B. J. (1999). Comparative in vitro and in vivo effects of antioxidants. Food Chem Toxicol, 37(9-10), 1015-1025.
Archbald, R. M. (1946). Enzymatic methods in amino acid analysis. Ann N Y Acad Sci, 47, 181-186.
Armstead, W. M., Mirro, R., Busija, D. W., &; Leffler, C. W. (1988). Postischemic generation of superoxide anion by newborn pig brain. Am J Physiol, 255(2 Pt 2), H401-403.
Baur, J. A., &; Sinclair, D. A. (2006). Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov, 5(6), 493-506.
Bennett, R. A., Wilson, D. M., Wong, D., &; Demple, B. (1997). Interaction of human apurinic endonuclease and DNA polymerase beta in the base excision repair pathway. Proc Natl Acad Sci U S A, 94(14), 7166-7169.
Bergeron, M., Gidday, J. M., Yu, A. Y., Semenza, G. L., Ferriero, D. M., &; Sharp, F. R. (2000). Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain. Ann Neurol, 48(3), 285-296.
Bergeron, M., Yu, A. Y., Solway, K. E., Semenza, G. L., &; Sharp, F. R. (1999). Induction of hypoxia-inducible factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain. Eur J Neurosci, 11(12), 4159-4170.
Boveris, A., &; Chance, B. (1973). The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J, 134(3), 707-716.
Bederson, J. B., Pitts, L. H., Germano, S. M., Nishimura, M. C., Davis, R. L., &; Bartkowski, H. M. (1986). Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke, 17(6), 1304-1308.
Calkins, M. J., Jakel, R. J., Johnson, D. A., Chan, K., Kan, Y. W., &; Johnson, J. A. (2005). Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc Natl Acad Sci U S A, 102(1), 244-249.
Chan, P. H. (1994). Oxygen radicals in focal cerebral ischemia. Brain Pathol, 4(1), 59-65.
Chan, P. H. (2001). Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab, 21(1), 2-14.
Chang, T. T., &; Chou, W. N. (1995). Antrodia cinnamomea sp. nov. on Cinnamomum kanehirai in Taiwan. Mycological Research, 99, 756-758.
Chang, Y., Hsiao, G., Chen, S. H., Chen, Y. C., Lin, J. H., Lin, K. H., Chou, D. S., &; Sheu, J. R. (2007). Tetramethylpyrazine suppresses HIF-1alpha, TNF-alpha, and activated caspase-3 expression in middle cerebral artery occlusion-induced brain ischemia in rats. Acta Pharmacol Sin, 28(3), 327-333.
Chen, C. C., Shiao, Y. J., Lin, R. D., Shao, Y. Y., Lai, M. N., Lin, C. C., Ng, L. T., &; Kuo, Y. H. (2006). Neuroprotective diterpenes from the fruiting body of Antrodia camphorata. J Nat Prod, 69(4), 689-691.
Chen, C., Hu, Q., Yan, J., Lei, J., Qin, L., Shi, X., Luan, L., Yang, L., Wang, K., Han, J., Nanda, A., &; Zhou, C. (2007a). Multiple effects of 2ME2 and D609 on the cortical expression of HIF-1alpha and apoptotic genes in a middle cerebral artery occlusion-induced focal ischemia rat model. J Neurochem, 102(6), 1831-1841.
Chen, C. C., Liu, Y. W., Ker, Y. B., Wu, Y. Y., Lai, E. Y., Chyau, C. C., Hseu, T. H., &; Peng, R. Y. (2007b). Chemical characterization and anti-inflammatory effect of polysaccharides fractionated from submerge-cultured Antrodia camphorata mycelia. J Agric Food Chem, 55(13), 5007-5012.
Chen, Y. C., Liu, Y. L., Li, F. Y., Chang, C. I., Wang, S. Y., Lee, K. Y., Li, S. L., Chen, Y. P., Jinn, T. R., &; Tzen, J. T. (2011). Antcin A, a steroid-like compound from Antrodia camphorata, exerts anti-inflammatory effect via mimicking glucocorticoids. Acta Pharmacol Sin, 32(7), 904-911.
Chen, Y. S., Zhu, X. X., Zhao, X. Y., Xing, H. Y., &; Li, Y. G. (2008). Hemin, a heme oxygenase-1 inducer, improves aortic endothelial dysfunction in insulin resistant rats. Chin Med J (Engl), 121(3), 241-247.
Clemens, J. A., Ho, P. P., &; Panetta, J. A. (1991). LY178002 reduces rat brain damage after transient global forebrain ischemia. Stroke, 22(8), 1048-1052.
Cuzzocrea, S., McDonald, M. C., Mazzon, E., Siriwardena, D., Costantino, G., Fulia, F., Cucinotta, G., Gitto, E., Cordaro, S., Barberi, I., De Sarro, A., Caputi, A. P., &; Thiemermann, C. (2000). Effects of tempol, a membrane-permeable radical scavenger, in a gerbil model of brain injury. Brain Res, 875(1-2), 96-106.
Chung, S., Yao, H., Caito, S., Hwang, J. W., Arunachalam, G., &; Rahman, I. (2010). Regulation of SIRT1 in cellular functions: role of polyphenols. Arch Biochem Biophys, 501(1), 79-90.
del Zoppo, G., Ginis, I., Hallenbeck, J. M., Iadecola, C., Wang, X., &; Feuerstein, G. Z. (2000). Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol, 10(1), 95-112.
Dirnagl, U., Iadecola, C., &; Moskowitz, M. A. (1999). Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci, 22(9), 391-397.
Dore, S., Takahashi, M., Ferris, C. D., Zakhary, R., Hester, L. D., Guastella, D., &; Snyder, S. H. (1999). Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury. Proc Natl Acad Sci U S A, 96(5), 2445-2450.
Elson, D. A., Thurston, G., Huang, L. E., Ginzinger, D. G., McDonald, D. M., Johnson, R. S., &; Arbeit, J. M. (2001). Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1alpha. Genes Dev, 15(19), 2520-2532.
Emamaullee, J. A., &; Shapiro, A. M. (2006). Interventional strategies to prevent beta-cell apoptosis in islet transplantation. Diabetes, 55(7), 1907-1914.
Esterbauer, H., &; Cheeseman, K. H. (1990). Determination of aldehydic lipid peroxidation products: Malonaldehyde and 4-hydroxynonenal. Methods Enzymol, 186, 407-421.
Fisher, M., &; Schaebitz, W. (2000). An overview of acute stroke therapy: past, present, and future. Arch Intern Med, 160(21), 3196-3206.
Flamm, E. S., Demopoulos, H. B., Seligman, M. L., Poser, R. G., &; Ransohoff, J. (1978). Free radicals in cerebral ischemia. Stroke, 9(5), 445-447.
Foulkes, M. A., Wolf, P. A., Price, T. R., Mohr, J. P., &; Hier, D. B. (1988). The Stroke Data Bank: design, methods, and baseline characteristics. Stroke, 19(5), 547-554.
Fujimura, M., Morita-Fujimura, Y., Kawase, M., &; Chan, P. H. (1999). Early decrease of apurinic/apyrimidinic endonuclease expression after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab, 19(5), 495-501.
Fuson, K. S., Mark, R. J., Panetta, J. A., &; May, P. C. (1999). Characterization of LY231617 protection against hydrogen peroxide toxicity. J Neurochem, 72(3), 1154-1160.
Feng, Z., &; Zhang, J. T. (2004). Protective effect of melatonin on beta-amyloid-induced apoptosis in rat astroglioma C6 cells and its mechanism. Free Radic Biol Med, 37(11), 1790-1801.
Gasche, Y., Fujimura, M., Morita-Fujimura, Y., Copin, J. C., Kawase, M., Massengale, J., &; Chan, P. H. (1999). Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood-brain barrier dysfunction. J Cereb Blood Flow Metab, 19(9), 1020-1028.
Geethangili, M., &; Tzeng, Y. M. (2011). Review of Pharmacological Effects of Antrodia camphorata and Its Bioactive Compounds. Evid Based Complement Alternat Med, 2011, 212641.
Goldring, C. E., Kitteringham, N. R., Jenkins, R., Lovatt, C. A., Randle, L. E., Abdullah, A., Owen, A., Liu, X., Butler, P. J., Williams, D. P., Metcalfe, P., Berens, C., Hillen, W., Foster, B., Simpson, A., McLellan, L., &; Park, B. K. (2006). Development of a transactivator in hepatoma cells that allows expression of phase I, phase II, and chemical defense genes. Am J Physiol Cell Physiol, 290(1), C104-115.
Gan, L. (2007). Therapeutic potential of sirtuin-activating compounds in Alzheimer's disease. Drug News Perspect, 20(4), 233-239.
Hall, E. D., &; Braughler, J. M. (1989). Central nervous system trauma and stroke. II. Physiological and pharmacological evidence for involvement of oxygen radicals and lipid peroxidation. Free Radic Biol Med, 6(3), 303-313.
Halliwell, B., &; Gutteridge, J. M. (1984). Lipid peroxidation, oxygen radicals, cell damage, and antioxidant therapy. Lancet, 1(8391), 1396-1397.
Halliwell, B., &; Gutteridge, J. M. C. (1999). The chemisty of free radicals and related reactive species. Free Radicals in Biology and Medicine, 36-104.
Harikumar, K. B., &; Aggarwal, B. B. (2008). Resveratrol: a multitargeted agent for age-associated chronic diseases. Cell Cycle, 7(8), 1020-1035.
Hsieh, Y. H., Chu, F. H., Wang, Y. S., Chien, S. C., Chang, S. T., Shaw, J. F., Chen, C. Y., Hsiao, W. W., Kuo, Y. H., &; Wang, S. Y. (2010). Antrocamphin A, an anti-inflammatory principal from the fruiting body of Taiwanofungus camphoratus , and its mechanisms. J Agric Food Chem, 58(5), 3153-3158.
Huang, N. K., Cheng, J. J., Lai, W. L., &; Lu, M. K. (2005). Antrodia camphorata prevents rat pheochromocytoma cells from serum deprivation-induced apoptosis. FEMS Microbiol Lett, 244(1), 213-219.
Hansen, M. B., Nielsen, S. E., &; Berg, K. (1989). Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J Immunol Methods, 119(2), 203-210.
Ikemune, K., Mitani, A., Namba, S., Kataoka, K., &; Arai, T. (1999). Functional changes of N-methyl-D-aspartic acid and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate channels in gerbil hippocampal CA1, in relation to postischemic enhancement of glutamate receptor-mediated responses. Neurosci Lett, 275(2), 125-128.
Ishii, T., Itoh, K., Takahashi, S., Sato, H., Yanagawa, T., Katoh, Y., Bannai, S., &; Yamamoto, M. (2000). Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem, 275(21), 16023-16029.
Jacob, P., Fesenko, S., Firsakova, S. K., Likhtarev, I. A., Schotola, C., Alexakhin, R. M., Zhuchenko, Y. M., Kovgan, L., Sanzharova, N. I., &; Ageyets, V. (2001). Remediation strategies for rural territories contaminated by the Chernobyl accident. J Environ Radioact, 56(1-2), 51-76.
Jiang, D., Jha, N., Boonplueang, R., &; Andersen, J. K. (2001). Caspase 3 inhibition attenuates hydrogen peroxide-induced DNA fragmentation but not cell death in neuronal PC12 cells. J Neurochem, 76(6), 1745-1755.
Jones, N. M., Lee, E. M., Brown, T. G., Jarrott, B., &; Beart, P. M. (2006). Hypoxic preconditioning produces differential expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and its regulatory enzyme HIF prolyl hydroxylase 2 in neonatal rat brain. Neurosci Lett, 404(1-2), 72-77.
Jung, J. Y., Roh, K. H., Jeong, Y. J., Kim, S. H., Lee, E. J., Kim, M. S., Oh, W. M., Oh, H. K., &; Kim, W. J. (2008). Estradiol protects PC12 cells against CoCl2-induced apoptosis. Brain Res Bull, 76(6), 579-585.
Kerendi, F., Halkos, M. E., Kin, H., Corvera, J. S., Brat, D. J., Wagner, M. B., Vinten-Johansen, J., Zhao, Z. Q., Forbess, J. M., Kanter, K. R., Kelley, M. E., &; Kirshbom, P. M. (2005). Upregulation of hypoxia inducible factor is associated with attenuation of neuronal injury in neonatal piglets undergoing deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg, 130(4), 1079.
Kim, H. J., &; Vaziri, N. D. (2010). Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure. Am J Physiol Renal Physiol, 298(3), F662-671.
Kontos, H. A. (1985). George E. Brown memorial lecture. Oxygen radicals in cerebral vascular injury. Circ Res, 57(4), 508-516.
LaManna, J. C., Chavez, J. C., &; Pichiule, P. (2004). Structural and functional adaptation to hypoxia in the rat brain. J Exp Biol, 207(Pt 18), 3163-3169.
Lawrence, R. A., &; Burk, R. F. (1976). Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun, 71(4), 952-958.
Lee, J. M., Calkins, M. J., Chan, K., Kan, Y. W., &; Johnson, J. A. (2003). Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol Chem, 278(14), 12029-12038.
Lewen, A., Matz, P., &; Chan, P. H. (2000). Free radical pathways in CNS injury. J Neurotrauma, 17(10), 871-890.
Lipton, P. (1999). Ischemic cell death in brain neurons. Physiol Rev, 79(4), 1431-1568.
Liu, D. Z., Liang, Y. C., Lin, S. Y., Lin, Y. S., Wu, W. C., Hou, W. C., &; Su, C. H. (2007a). Antihypertensive activities of a solid-state culture of Taiwanofungus camphoratus (Chang-chih) in spontaneously hypertensive rats. Biosci Biotechnol Biochem, 71(1), 23-30.
Liu, D. Z., Liang, H. J., Chen, C. H., Su, C. H., Lee, T. H., Huang, C. T., Hou, W. C., Lin, S. Y., Zhong, W. B., Lin, P. J., Hung, L. F., &; Liang, Y. C. (2007b). Comparative anti-inflammatory characterization of wild fruiting body, liquid-state fermentation, and solid-state culture of Taiwanofungus camphoratus in microglia and the mechanism of its action. J Ethnopharmacol, 113(1), 45-53.
Love, S. (1999). Oxidative stress in brain ischemia. Brain Pathol, 9(1), 119-131.
Lowry, O. H., Rosebrough, N. J., Farr, A. L., &; Randall, R. J. (1951). Protein measurement with the Folin phenol reagent. J Biol Chem, 193(1), 265-275.
Lan, A., Liao, X., Mo, L., Yang, C., Yang, Z., Wang, X., Hu, F., Chen, P., Feng, J., Zheng, D., &; Xiao, L. (2011). Hydrogen sulfide protects against chemical hypoxia-induced injury by inhibiting ROS-activated ERK1/2 and p38MAPK signaling pathways in PC12 cells. PLoS One, 6(10), e25921.
Lin, C. W., Wu, M. J., Liu, I. Y., Su, J. D., &; Yen, J. H. (2010). Neurotrophic and cytoprotective action of luteolin in PC12 cells through ERK-dependent induction of Nrf2-driven HO-1 expression. J Agric Food Chem, 58(7), 4477-4486.
LeBel, C. P., Ischiropoulos, H., &; Bondy, S. C. (1992). Evaluation of the probe 2',7'-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem Res Toxicol, 5(2), 227-231.
Martin, C., Yu, A. Y., Jiang, B. H., Davis, L., Kimberly, D., Hohimer, A. R., &; Semenza, G. L. (1998). Cardiac hypertrophy in chronically anemic fetal sheep: Increased vascularization is associated with increased myocardial expression of vascular endothelial growth factor and hypoxia-inducible factor 1. Am J Obstet Gynecol, 178(3), 527-534.
Mizuno, T., Kinoshita, T., Zhuang, C., Ito, H., &; Mayuzumi, Y. (1995). Antitumor-active heteroglycans from niohshimeji mushroom, Tricholoma giganteum. Biosci Biotechnol Biochem, 59(4), 568-571.
Morale, M. C., Serra, P. A., L'Episcopo, F., Tirolo, C., Caniglia, S., Testa, N., Gennuso, F., Giaquinta, G., Rocchitta, G., Desole, M. S., Miele, E., &; Marchetti, B. (2006). Estrogen, neuroinflammation and neuroprotection in Parkinson's disease: glia dictates resistance versus vulnerability to neurodegeneration. Neuroscience, 138(3), 869-878.
Morioka, T., Kalehua, A. N., &; Streit, W. J. (1991). The microglial reaction in the rat dorsal hippocampus following transient forebrain ischemia. J Cereb Blood Flow Metab, 11(6), 966-973.
Morrissey, P. A., &; O'Brien, N. M. (1998). ”Dietary antioxidants in health and disease”. Int. Dairy J., 8, 463-472.
Mu, D., Jiang, X., Sheldon, R. A., Fox, C. K., Hamrick, S. E., Vexler, Z. S., &; Ferriero, D. M. (2003). Regulation of hypoxia-inducible factor 1alpha and induction of vascular endothelial growth factor in a rat neonatal stroke model. Neurobiol Dis, 14(3), 524-534.
Margaill, I., Plotkine, M., &; Lerouet, D. (2005). Antioxidant strategies in the treatment of stroke. Free Radic Biol Med, 39(4), 429-443.
Mangoura, D., Sakellaridis, N., Jones, J., &; Vernadakis, A. (1989). Early and late passage C-6 glial cell growth: similarities with primary glial cells in culture. Neurochem Res, 14(10), 941-947.
Nakamura, T., &; Lipton, S. A. (2007). Molecular mechanisms of nitrosative stress-mediated protein misfolding in neurodegenerative diseases. Cell Mol Life Sci, 64(13), 1609-1620.
Nitatori, T., Sato, N., Waguri, S., Karasawa, Y., Araki, H., Shibanai, K., Kominami, E., &; Uchiyama, Y. (1995). Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J Neurosci, 15(2), 1001-1011.
Okamoto, H., Ito, O., Roman, R. J., &; Hudetz, A. G. (1998). Role of inducible nitric oxide synthase and cyclooxygenase-2 in endotoxin-induced cerebral hyperemia. Stroke, 29(6), 1209-1218.
Oh, ES., Baek, KH., Lee, WY., Oh, KW., Kim, HS., Han, JH., Lee, KW., Son, HY., Kang, SK., &; Kang, M. (2006). The Effect of Oxidative Stress on the Proliferation and Differentiation of Human Bone Marrow Stromal Cell-Derived Osteoblasts. J Korean Soc Endocrinol, 21(3), 222-232.
Paglia, D. E., &; Valentine, W. N. (1967). Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med, 70(1), 158-169.
Pehar, M., Vargas, M. R., Robinson, K. M., Cassina, P., Diaz-Amarilla, P. J., Hagen, T. M., Radi, R., Barbeito, L., &; Beckman, J. S. (2007). Mitochondrial superoxide production and nuclear factor erythroid 2-related factor 2 activation in p75 neurotrophin receptor-induced motor neuron apoptosis. J Neurosci, 27(29), 7777-7785.
Puttaraju, N. G., Venkateshaiah, S. U., Dharmesh, S. M., Urs, S. M., &; Somasundaram, R. (2006). Antioxidant activity of indigenous edible mushrooms. J Agric Food Chem, 54(26), 9764-9772.
Parker, K. K., Norenberg, M. D., &; Vernadakis, A. (1980). "Transdifferentiation" of C6 glial cells in culture. Science, 208(4440), 179-181.
Quincozes-Santos, A., Andreazza, A. C., Goncalves, C. A., &; Gottfried, C. (2010). Actions of redox-active compound resveratrol under hydrogen peroxide insult in C6 astroglial cells. Toxicol In Vitro, 24(3), 916-920.
Qiao, H., Dong, L., Zhang, X., Zhu, C., Wang, L., Liu, Z., Chen, L., Xing, Y., Wang, C., &; Li, Y. (2012). Protective effect of luteolin in experimental ischemic stroke: upregulated SOD1, CAT, Bcl-2 and claudin-5, down-regulated MDA and Bax expression. Neurochem Res, 37(9), 2014-2024.
Ran, R., Xu, H., Lu, A., Bernaudin, M., &; Sharp, F. R. (2005). Hypoxia preconditioning in the brain. Dev Neurosci, 27(2-4), 87-92.
Ren, J., Fan, C., Chen, N., Huang, J., &; Yang, Q. (2011). Resveratrol pretreatment attenuates cerebral ischemic injury by upregulating expression of transcription factor Nrf2 and HO-1 in rats. Neurochem Res, 36(12), 2352-2362.
Rukenstein, A., Rydel, R. E., &; Greene, L. A. (1991). Multiple agents rescue PC12 cells from serum-free cell death by translation- and transcription-independent mechanisms. J Neurosci, 11(8), 2552-2563.
Satoh, T., Kosaka, K., Itoh, K., Kobayashi, A., Yamamoto, M., Shimojo, Y., Kitajima, C., Cui, J., Kamins, J., Okamoto, S., Izumi, M., Shirasawa, T., &; Lipton, S. A. (2008). Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1. J Neurochem, 104(4), 1116-1131.
Satoh, T., Okamoto, S. I., Cui, J., Watanabe, Y., Furuta, K., Suzuki, M., Tohyama, K., &; Lipton, S. A. (2006). Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic [correction of electrophillic] phase II inducers. Proc Natl Acad Sci U S A, 103(3), 768-773.
Semenza, G. L. (1998). Hypoxia-inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev, 8(5), 588-594.
Semenza, G. L. (2000). HIF-1 and human disease: one highly involved factor. Genes Dev, 14(16), 1983-1991.
Semenza, G. L. (2001). Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. Trends Mol Med, 7(8), 345-350.
Sharp, F. R., Lu, A., Tang, Y., &; Millhorn, D. E. (2000). Multiple molecular penumbras after focal cerebral ischemia. J Cereb Blood Flow Metab, 20(7), 1011-1032.
Sharp, F. R., Ran, R., Lu, A., Tang, Y., Strauss, K. I., Glass, T., Ardizzone, T., &; Bernaudin, M. (2004). Hypoxic preconditioning protects against ischemic brain injury. NeuroRx, 1(1), 26-35.
Shih, A. Y., Johnson, D. A., Wong, G., Kraft, A. D., Jiang, L., Erb, H., Johnson, J. A., &; Murphy, T. H. (2003). Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci, 23(8), 3394-3406.
Shih, A. Y., Li, P., &; Murphy, T. H. (2005). A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo. J Neurosci, 25(44), 10321-10335.
Shin, J. A., Lee, H., Lim, Y. K., Koh, Y., Choi, J. H., &; Park, E. M. (2010). Therapeutic effects of resveratrol during acute periods following experimental ischemic stroke. J Neuroimmunol, 227(1-2), 93-100.
Siddiq, A., Ayoub, I. A., Chavez, J. C., Aminova, L., Shah, S., LaManna, J. C., Patton, S. M., Connor, J. R., Cherny, R. A., Volitakis, I., Bush, A. I., Langsetmo, I., Seeley, T., Gunzler, V., &; Ratan, R. R. (2005). Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system. J Biol Chem, 280(50), 41732-41743.
Siesjo, B. K., Agardh, C. D., &; Bengtsson, F. (1989). Free radicals and brain damage. Cerebrovasc Brain Metab Rev, 1(3), 165-211.
Simao, F., Matte, A., Matte, C., Soares, F. M., Wyse, A. T., Netto, C. A., &; Salbego, C. G. (2011). Resveratrol prevents oxidative stress and inhibition of Na(+)K(+)-ATPase activity induced by transient global cerebral ischemia in rats. J Nutr Biochem, 22(10), 921-928.
Simao, F., Matte, A., Pagnussat, A. S., Netto, C. A., &; Salbego, C. G. (2012). Resveratrol preconditioning modulates inflammatory response in the rat hippocampus following global cerebral ischemia. Neurochem Int, 61(5), 659-665.
Soehle, M., Heimann, A., &; Kempski, O. (1998). Postischemic application of lipid peroxidation inhibitor U-101033E reduces neuronal damage after global cerebral ischemia in rats. Stroke, 29(6), 1240-1246; discussion 1246-1247.
Song, T. Y., &; Yen, G. C. (2002). Antioxidant properties of Antrodia camphorata in submerged culture. J Agric Food Chem, 50(11), 3322-3327.
Sun, A. Y., &; Chen, Y. M. (1998). Oxidative stress and neurodegenerative disorders. J Biomed Sci, 5(6), 401-414.
Salim, S., Ahmad, M., Zafar, K. S., Ahmad, A. S., &; Islam, F. (2003). Protective effect of Nardostachys jatamansi in rat cerebral ischemia. Pharmacol Biochem Behav, 74(2), 481-486.
Tsai, Z. T., &; Liaw, S. L. (1982). The use and the effect of Ganoderma. San Yun Press, 116-117.
Vincent, K. A., Shyu, K. G., Luo, Y., Magner, M., Tio, R. A., Jiang, C., Goldberg, M. A., Akita, G. Y., Gregory, R. J., &; Isner, J. M. (2000). Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1alpha/VP16 hybrid transcription factor. Circulation, 102(18), 2255-2261.
Whittemore, E. R., Loo, D. T., &; Cotman, C. W. (1994). Exposure to hydrogen peroxide induces cell death via apoptosis in cultured rat cortical neurons. Neuroreport, 5(12), 1485-1488.
Wu, S. H., Leif, R., &; Chang, T. T. (1997). Antrodia camphorate (“niu-chang-chih”), new combination of a medicinal fungus in Taiwan. Bot. Bull. Acad. Sin., 38, 56-64.
Yang, B. C., Lin, H. K., Hor, W. S., Hwang, J. Y., Lin, Y. P., Liu, M. Y., &; Wang, Y. J. (2003). Mediation of enhanced transcription of the IL-10 gene in T cells, upon contact with human glioma cells, by Fas signaling through a protein kinase A-independent pathway. J Immunol, 171(8), 3947-3954.
Yang, C., Zhang, X., Fan, H., &; Liu, Y. (2009). Curcumin upregulates transcription factor Nrf2, HO-1 expression and protects rat brains against focal ischemia. Brain Res, 1282, 133-141.
Yang, H. L., Hseu, Y. C., Chen, J. Y., Yech, Y. J., Lu, F. J., Wang, H. H., Lin, P. S., &; Wang, B. C. (2006). Antrodia camphorata in submerged culture protects low density lipoproteins against oxidative modification. Am J Chin Med, 34(2), 217-231.
Yeh, C. T., Rao, Y. K., Yao, C. J., Yeh, C. F., Li, C. H., Chuang, S. E., Luong, J. H., Lai, G. M., &; Tzeng, Y. M. (2009). Cytotoxic triterpenes from Antrodia camphorata and their mode of action in HT-29 human colon cancer cells. Cancer Lett, 285(1), 73-79.
Yoshida, H., Kong, Y. Y., Yoshida, R., Elia, A. J., Hakem, A., Hakem, R., Penninger, J. M., &; Mak, T. W. (1998). Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell, 94(6), 739-750.
Yrjanheikki, J., Koistinaho, J., Copin, J. C., de Crespigny, A., Moseley, M. E., &; Chan, P. H. (2000). Spreading depression-induced expression of c-fos and cyclooxygenase-2 in transgenic mice that overexpress human copper/zinc-superoxide dismutase. J Neurotrauma, 17(8), 713-718.
Zang, M., &; Su, C. H. (1990). “Ganoderma comphoratum, a new taxon in genus Ganoderma from Taiwan” Acta Bot. Yunnanica, 12, 93-396.
Zou, H., Henzel, W. J., Liu, X., Lutschg, A., &; Wang, X. (1997). Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell, 90(3), 405-413.
Zhu, L. H., Bi, W., Qi, R. B., Wang, H. D., &; Lu, D. X. (2011). Luteolin inhibits microglial inflammation and improves neuron survival against inflammation. Int J Neurosci, 121(6), 329-336