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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 潘子明 | |
dc.contributor.author | Wei-Ting Tseng | en |
dc.contributor.author | 曾暐婷 | zh_TW |
dc.date.accessioned | 2021-06-15T13:27:20Z | - |
dc.date.available | 2021-02-24 | |
dc.date.copyright | 2016-02-24 | |
dc.date.issued | 2016 | |
dc.date.submitted | 2016-02-16 | |
dc.identifier.citation | 林讚峰。1994。紅麴菌的特性及應用。生物產業。5: 29-35。
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/51201 | - |
dc.description.abstract | 現今社會人口逐漸趨向老化,相對地在醫療系統上老化疾病的治療需求也日漸攀升,較常見的老化疾病為阿茲海默症及帕金森氏症。帕金森氏症目前致病機轉雖尚未完全了解,但其患者多為腦中黑質緻密處之多巴胺神經元受損,使其無法產生多巴胺神經傳導物質,故此疾病治療方式為給予多巴胺前趨物 levodopa,但此藥物只在療程初期有效,因此發展新的有效成分應是保健食品改善帕金森氏症之重要研究方向。研究指出帕金森氏症患者腦中多巴胺神經元受損,其氧化壓力扮演重要角色,而抑制其氧化壓力所造成的細胞凋亡大多利用抗氧化物質來進行相關研究。紅麴米多年來為中國傳統醫藥及保健食品使用,由紅麴米可分離出高抗氧化能力的 dimerumic acid (DMA) 及 deferricoprogen (DFC),以及可抑制細胞氧化壓力的 monascin (MS) 及 ankaflavin (AK),故本研究評估紅麴發酵產物對帕金森氏症之改善效果。細胞試驗結果顯示,紅麴發酵產物中之 DMA 及 DFC 能使 6-hydroxydopamine (6-OHDA) 誘導 PC-12 細胞內 NADPH oxidase-2 (NOX-2) 蛋白表現量下降,使其胞內及胞外的活性氧自由基 (reactive oxygen species, ROS) 下降,且會透過調節 Bcl-2 associated X protein (Bax) 及 Bcl-2 蛋白質表現量,降低 caspase-3 的活性,使受損的分化後 PC-12 細胞凋亡數減少,達到保護神經細胞之作用。動物試驗以含有 DMA 及 DFC 之 50% 紅麴米酒精萃取物 (red mold rice extract with 50% ethanol, R50E) 來評估其對於 6-OHDA 誘導帕金森氏症大鼠之改善效果。實驗結果顯示,每 1 克 R50E 中含有 2.76 mg DMA 及 10.95 mg DFC。餵食 R50E (5.5 或 11.0 mg/kg) 可改善 6-OHDA 誘導帕金森氏症大鼠之運動障礙,並降低腦中黑質緻密處多巴胺神經元之衰退。R50E 可藉由提升腦中超氧歧化酶 (superoxide dismutase, SOD)、過氧化氫酶 (catalase, CAT)、穀胱甘肽還原酶 (glutathione reductase, GR) 及穀胱甘肽過氧化物酶 (glutathione peroxidase, GPx) 之活性,與調控 p47 phox、NOX1 及 NOX2 之 mRNA 表現量,來降低 6-OHDA 誘導帕金森氏症大鼠腦中活性氧自由基 (ROS) 及丙二醛 (malondialdehyde, MDA) 之含量。除此之外,R50E 亦可抑制 6-OHDA 誘導帕金森氏症大鼠腦中發炎因子一氧化氮 (nitric oxide, NO) 及腫瘤壞死因子 (tumor necrosis factors, TNF-α) 之含量。以上結果顯示,R50E 可透過抗氧化及抗發炎機制來防止大腦中多巴胺神經元之衰退,具有潛力應用於帕金森氏症之改善。DFC 及 DMA 亦可降低 6-OHDA 誘導大鼠中腦初代細胞 (mesencephalic neuron) 及 SH-SY5Y人類神經母細胞凋亡,DMA 可能透過調控 N-methyl-D-aspartate (NMDA) 受體及同型二聚體醣蛋白,DFC 則可能透過調控免疫球蛋白 Fc 受體,進而促進 protein kinase B (Akt) 及 extracellular signal-regulated kinases (ERK) 蛋白磷酸化,抑制 p38 及 c-Jun N-terminal Kinase (JNK) 蛋白活化,此外,DMA 及 DFC 亦可提升 heme oxygenase-1 (HO-1) 蛋白質表現,使受損 SH-SY5Y 神經細胞凋亡數減少,達到保護神經細胞之作用。 | zh_TW |
dc.description.abstract | Society population is gradually moving towards aging. Relatively, demand for the treatment of aging diseases on the health care system has become more climb. The most common age-related neurodegenerative diseases are Alzheimer’s disease (AD) and Parkinson’s disease (PD). PD was found to be the loss of dopaminergic in the substantia nigra pars compacta (SNpc). Oral administration of levodopa remains the gold standard therapy for PD. But it is only effective for symptomatic relief during early stage of PD. There is therefore a great need to develop a new therapy for PD. Although the mechanisms responsible for dopaminergic death are not fully understood, accumulating evidence from studies suggests that oxidative stress plays the key role in initiating this cell death process. The presence of antioxidants protected against neuronal degeneration in dopamine neuron. Monascus purpureus-fermented rice, a traditional Chinese medicine as well as health food, includes multifunctional metabolites. M. purpureus-fermented products containing antioxidants: dimerumic acid (DMA) and deferricoprogen (DFC). We also found anti-oxidative stress compound-monascin (MS) and ankaflavin (AK) in Monascus- fermented secondary metabolites. Hence, the study used Monascus-fermented secondary metabolites to evaluate the improving effect on PD. In vitro, DMA and DFC reduced 6-hydroxydopamine (6-OHDA)-induced formation of extracellular and intercellular reactive oxygen species (ROS) and decreased NADPH oxidase-2 expression in differentiated PC-12 cells. DMA and DFC inhibited 6-OHDA-induced apoptosis and decreased activation of caspase-3 via regulation of Bcl-2 associated X protein (Bax) and Bcl-2 protein expression in differentiated PC-12 cells. Therefore, DMA and DFC may protect against 6-OHDA toxicity by inhibiting ROS formation and apoptosis. In vivo, the present study was designed to investigate the effects of antioxidant-containing M. purpureus NTU 568-fermented rice extract (extracted with 50% ethanol, so called R50E) in a 6-OHDA-induced neurotoxicity in rats. R50E contained 2.76 mg of DMA and 10.95 mg of DFC per 1 g of freeze-dried extract. Administration of R50E (5.5 or 11.0 mg/kg) reduced parkinsonian motor dysfunction and the number of tyrosine hydroxylase (TH)-immunoreative neurons present in 6-OHDA-induced lesioned rats. Moreover, administration of R50E reversed the elevation of ROS and malondialdehyde (MDA) levels and promoted the activity of antioxidant enzymes such as superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase via down-regulation of p47 phox, NOX1, and NOX2 expression in the 6-OHDA-lesion rats. Furthermore, treatment with R50E attenuated nitric oxide (NO) and tumor necrosis factors (TNF-α) levels in the 6-OHDA-lesion rats. In conclusion, R50E may prevent neurodegeration via anti-oxidative and anti-inflammatory mechanisms, suggesting its potential therapeutic value for PD treatment. DMA and DFC also inhibited 6-OHDA-induced apoptosis in mesencephalic neurons and SH-SY5Y cells. The protect effects of DMA and DFC may result from activation of protein kinase B (Akt) and extracellular signal-regulated kinases (ERK) pathway and inhibited the phoshorylation of p38 and c-Jun N-terminal Kinase (JNK) pathway. In addition, DMA and DFC may regulate N-methyl-D-aspartate (NMDA) receptor, homodimeric glycoprotein, and immunoglobulin Fc receptor gene, respectively. These results suggested that the neuroprotection elicted by DMA and DFC against 6-OHDA-induced neurotoxicity was associated with Akt, MAPK, and heme oxygenase-1 (HO-1) pathway through NMDA receptor, homodimeric glycoprotein, and immunoglobulin Fc receptor. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T13:27:20Z (GMT). No. of bitstreams: 1 ntu-105-D00b22010-1.pdf: 5302820 bytes, checksum: d8394b4d368f5b5397ec25397eaf3b30 (MD5) Previous issue date: 2016 | en |
dc.description.tableofcontents | 頁碼
目錄--------------------------------------------------------------------------------------I 圖目錄------------------------------------------------------------------------------------VIII 表目錄------------------------------------------------------------------------------------XII 縮寫表-----------------------------------------------------------------------------------XIII 化合物縮寫表-----------------------------------------------------------------------------------XVII 中文摘要--------------------------------------------------------------------------------------1 英文摘要--------------------------------------------------------------------------------------3 第壹章 文獻回顧----------------------------------------------------------------------------5 第一節 紅麴菌介紹-----------------------------------------------------------------------5 第二節 紅麴於食品上之應用-----------------------------------------------------------5 第三節 紅麴之功效研究-----------------------------------------------------------------6 一、紅麴米降膽固醇功效-------------------------------------------------------6 二、紅麴菌發酵產物抗疲勞功效----------------------------------------------7 三、紅麴山藥降膽固醇功效----------------------------------------------------7 四、紅麴發酵產物抑制阿茲海默症之類澱粉樣蛋白沉積與改善記憶學習功效------------------------------------------------------------------------ 8 1. 細胞模式----------------------------------------------------------------- 8 2. 動物模式--------------------------------------------------------- 9 五、紅麴萃取物降低體脂肪功效----------------------------------------------9 六、紅麴山藥降血壓功效------------------------------------------------------10 七、紅麴代謝產物抑制腫瘤生長及轉移功效------------------------------11 八、紅麴代謝產物改善糖尿病功效-----------------------------------------11 九、紅麴預防骨質酥鬆症功效-----------------------------------------------12 十、紅麴代謝產物改善酒精性脂肪肝功效---------------------------------12 第四節 紅麴發酵產物--------------------------------------------------------------13 一、膽固醇合成抑制劑―monacolins ---------------------------------------13 二、紅麴色素及azaphilone ---------------------------------------------------13 三、抗氧化物-dimerumic acid (DMA) 及deferricoprogen (DFC)-------16四、胺基酸類化合物------------------------------------------------------------16 五、黴菌毒素- citrinin --------------------------------------------------------18 第五節 帕金森氏症介紹----------------------------------------------------------------18 第六節 帕金森氏症之流行病學-------------------------------------------------------19 第七節 帕金森氏症之致病機轉-------------------------------------------------------21 第八節 帕金森氏症之治療-------------------------------------------------------------23 一、抗乙醯胺劑------------------------------------------------------------------23 二、左多巴製劑------------------------------------------------------------------23 三、多巴胺促效劑---------------------------------------------------------------23 四、單胺氧化酶抑制劑---------------------------------------------------------23 五、兒茶酚氧位甲基轉移酶抑制劑------------------------------------------24 第九節 帕金森氏症之研究模式-------------------------------------------------------24 一、6-Hydroxydipamine (6-OHDA)------------------------------------------24 二、1-Methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP)-------------24 第貳章 研究動機及實驗架構----------------------------------------------------------29 第一節 研究動機-------------------------------------------------------------------------29 第二節 實驗架構-------------------------------------------------------------------------31 第参章 材料與方法----------------------------------------------------------------------32 第一節 儀器及藥品----------------------------------------------------------------------32 一、儀器---------------------------------------------------------------------------32 二、藥品---------------------------------------------------------------------------32 第二節 實驗方法-------------------------------------------------------------------------33 一、 紅麴發酵產物改善 6-OHDA 誘導帕金森氏症細胞模式 (PC-12) 之功效篩選-----------------------------------------------------------------33 1. 紅麴米培養及其發酵產物之製備--------------------------------34 2. PC-12神經細胞培養------------------------------------------------35 3. MTT細胞存活率檢測----------------------------------------------35 4. 紅麴發酵產物對分化後PC-12細胞之毒性分析---------36 5. 6-OHDA誘導帕金森氏症細胞模式-----------------------------36 6. DNA片段檢測-------------------------------------------------------36 7. 細胞週期檢測--------------------------------------------------------36 8. Caspase-3活性分析-------------------------------------------------37 9. 胞內ROS生成量測定----------------------------------------------37 10. 6-OHDA 胞外自氧化檢測----------------------------------------37 11. 西方墨點法-----------------------------------------------------------38 12. 生物統計分析方法--------------------------------------------------38 二、紅麴發酵產物改善 6-OHDA 誘導帕金森氏症動物模式 (rat) 之探討-----------------------------------------------------------------------38 1. 實驗動物-------------------------------------------------------------39 2. 紅麴米之培養及其發酵產物之製備-------------------------------39 3. 50% 紅麴米酒精萃取物 (R50E) 中 DMA 及 DFC 含量之測定方法------------------------------------------------------------------40 4. 6-OHDA 帕金森氏症大鼠模式建立--------------------------------40 5. 擺盪能力行為測試-----------------------------------------------------42 6. 安全性指標之評估-----------------------------------------------------43 7. 組織病理切片染色-----------------------------------------------------43 8. 免疫組織化學染色----------------------------------------------------43 9. 腦中多巴胺含量分析--------------------------------------------------44 10. 腦組織處理------------------------------------------------------------44 11. 蛋白質濃度測定------------------------------------------------------45 12. ROS 含量分析--------------------------------------------------------45 13. 脂質過氧化指標分析------------------------------------------------45 14. 超氧歧化酵素活性測定---------------------------------------------45 15. Catalase 活性分析----------------------------------------------------46 16. Glutathione peroxidase (GPx) 活性分析--------------------------47 17. Glutathione reductase (GR) 活性分析----------------------------47 18. Nitric oxide (NO) 及 tumor necrosis factor-α (TNF-α) 發炎指標分析-------------------------------------------------------------------47 19. mRNA 表現量分析--------------------------------------------------47 20. 生物統計分析方法---------------------------------------------------48 三、紅麴發酵產物改善 6-OHDA 誘導帕金森氏症相關機轉之探討-----------------------------------------------------------------------------48 1. 大鼠中腦初代神經細胞 (mesencephalic neuron) 培養---------49 2. SH-SY5Y 人類神經母細胞培養-------------------------------------51 3. MTT細胞存活率檢測--------------------------------------------------51 4. 細胞凋亡之檢測 (Annexin V-FITC/PI雙染法分析)-------------51 5. 胞內ROS生成量測定-------------------------------------------------52 6. 蛋白質定量--------------------------------------------------------------52 7. 西方墨點法--------------------------------------------------------------52 8. DNA 微陣列 (microarray) 方法------------------------------------53 9. 生物統計分析方法-----------------------------------------------------53 第肆章 結果與討論----------------------------------------------------------------------55 第一節 紅麴發酵產物改善 6-OHDA 誘導帕金森氏症細胞模式 (PC-12) 之有效物質篩選-----------------------------------------------------------------55 一、紅麴發酵產物對於PC-12細胞存活率之影響------------------------55 二、6-OHDA對於PC-12細胞存活率之影響------------------------------57 三、紅麴發酵產物與6-OHDA共同處理對於PC-12細胞存活率之影響----------------------------------------------------------------------------57 四、NAC與6-OHDA共同處理對於PC-12細胞之影響----------------59 五、MS與6-OHDA共同處理對於PC-12細胞之影響------------------64 六、DFC與6-OHDA共同處理對於PC-12細胞之影響---------------64 七、DMA與6-OHDA共同處理對於PC-12細胞之影響---------------67 八、紅麴發酵產物與6-OHDA共同處理PC-12細胞對於氧化壓力之影響--------------------------------------------------------------------------67 1. 紅麴發酵產物與6-OHDA共同處理對於PC-12細胞內ROS含量之影響----------------------------------------------------------------69 2. 紅麴發酵產物對於6-OHDA胞外自氧化之影響----------------69 3. 紅麴發酵產物與6-OHDA 共同處理對於PC-12細胞內 NADPH oxidase (NOX) 含量之影響-------------------------------72 九、紅麴發酵產物與6-OHDA共同處理對於PC-12細胞凋亡之影響----------------------------------------------------------------------------------74 1. 6-OHDA誘導PC-12細胞凋亡---------------------------------------74 2. 紅麴發酵產物與6-OHDA共同處理PC-12影響細胞凋亡之程度-------------------------------------------------------------------------74 3. 紅麴發酵產物與6-OHDA共同處理PC-12細胞凋亡之路徑探討--------------------------------------------------------------------------76 (1) Caspase-3 活性----------------------------------------------------76 (2) 細胞內Bax 及 Bcl-2 蛋白質之表現-------------------------79 第二節 紅麴發酵產物改善 6-OHDA 誘導帕金森氏症動物模式 (rat) 之探討--------------------------------------------------------------------------------82 一、50% 紅麴米酒精萃取物 (R50E) 中 DMA 及 DFC 之含量---82 二、R50E 對於 6-OHDA 誘導帕金森氏症大鼠安全性之評估-85 三、R50E改善 6-OHDA 誘導帕金森氏症大鼠擺盪能力行為測試---85 四、R50E 改善6-OHDA 誘導帕金森氏症大鼠黑質緻密處多巴胺神經元之衰退----------------------------------------------------------------88 五、R50E 改善6-OHDA 誘導帕金森氏症大鼠紋狀體 (striatum) 多巴胺神經傳導物質 (dopamine) 之含量---------------------------90 六、R50E 對於 6-OHDA 誘導帕金森氏症大鼠腦紋狀體 (striatum) 氧化壓力指標之影響--------------------------------------------93 1. R50E 抑制 6-OHDA 誘導帕金森氏症大鼠腦中紋狀體之 ROS 與 MDA 含量----------------------------------------------------------93 2. R50E 改善 6-OHDA 誘導帕金森氏症大鼠腦中紋狀體抗氧化酶之含量-----------------------------------------------------------------95 七、R50E 調控6-OHDA 誘導帕金森氏症大鼠腦中黑質緻密處 NADPH oxidase (NOX) 之 mRNA表現量---------------------------95 八、R50E 抑制 6-OHDA 誘導帕金森氏症大鼠腦中紋狀體 GFAP 之表現量----------------------------------------------------------------------97 九、R50E 抑制 6-OHDA 誘導帕金森氏症大鼠腦中紋狀體發炎指標 NO 及 TNF-α 之含量--------------------------------------------------97 第三節 紅麴發酵產物改善6-OHDA 誘導帕金森氏症相關機轉之探討-100 一、6-OHDA對於大鼠中腦初代神經細胞 (mesencephalic neuron) 存 活率之影響----------------------------------------------------------------102 二、DMA 及 DFC 與6-OHDA共同處理對於中腦初代神經細胞存活率之影響-------------------------------------------------------------------102 1. DMA及DFC對於中腦初代神經細胞存活率之影響-----------102 2. DMA及DFC改善經 6-OHDA 誘導中腦初代神經細胞之存活---------------------------------------------------------------------------104 三、6-OHDA對於SH-SY5Y 人類神經母細胞存活率之影響---------104 四、DMA 及 DFC 與6-OHDA共同處理對於SH-SY5Y 細胞存活率之影響----------------------------------------------------------------------107 五、DMA 及 DFC 與6-OHDA共同處理對於 SH-SY5Y 細胞 ROS含量之影響---------------------------------------------------------------107 六、DMA 及 DFC 與6-OHDA共同處理對於 SH-SY5Y 細胞凋亡之影響-------------------------------------------------------------------------110 七、DMA 及 DFC 改善 6-OHDA 誘導 SH-SY5Y 細胞之相關機轉調控-------------------------------------------------------------------------110 1. Akt路徑----------------------------------------------------------------113 2. 促分裂原活化蛋白激酶 (mitogen-activated protein kinases, MAPKs) 路徑---------------------------------------------------------113 3. 第一型血色素氧化酵素 (heme oxygenase, HO-1) ------------118 4. DNA 微陣列分析-----------------------------------------------------118 第伍章 結論-------------------------------------------------------------------------------132 參考文獻-------------------------------------------------------------------------------------133 | |
dc.language.iso | zh-TW | |
dc.title | 紅麴發酵產物改善帕金森氏症之研究 | zh_TW |
dc.title | Study on Monascus-fermented products for improvement in Parkinson’s disease | en |
dc.type | Thesis | |
dc.date.schoolyear | 104-1 | |
dc.description.degree | 博士 | |
dc.contributor.oralexamcommittee | 周正俊,陳明汝,蔡宗佑,郭嘉信,謝淑貞 | |
dc.subject.keyword | 紅麴,帕金森氏症,氧化壓力,dimerumic acid,deferricoprogen, | zh_TW |
dc.subject.keyword | Monascus-fermented metabolite,Parkinson’s disease,oxidative stress,dimerumic acid,deferricoprogen, | en |
dc.relation.page | 148 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2016-02-16 | |
dc.contributor.author-college | 生命科學院 | zh_TW |
dc.contributor.author-dept | 生化科技學系 | zh_TW |
顯示於系所單位: | 生化科技學系 |
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