簡易檢索 / 詳目顯示

研究生: 林書安
Lin, Shu-An
論文名稱: 針對第三型小腦萎縮症探討神經發炎致病機制與具潛力的治療策略
Pathomechanism characterization and potential therapeutics identification for SCA3 targeting neuroinflammation
指導教授: 李桂楨
學位類別: 碩士
Master
系所名稱: 生命科學系
Department of Life Science
論文出版年: 2019
畢業學年度: 107
語文別: 中文
論文頁數: 80
中文關鍵詞: 第三型小腦萎縮症多麩醯胺微膠細胞神經發炎介白素-1β
英文關鍵詞: Spinocerebellar ataxia type 3, polyglutamine, microglia, neuroinflammation, IL-1β
DOI URL: http://doi.org/10.6345/NTNU201901042
論文種類: 學術論文
相關次數: 點閱:145下載:0
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報
  • 多麩醯胺(PolyQ)介導的脊髓小腦共濟失調症(SCA)是由於基因編碼序列中,擴增CAG的重複突變所引起。PolyQ蛋白的錯誤折疊和聚集導致毒性增加,是發病機制的核心,並且伴隨著活性氧化物(ROS)的產生和細胞毒性的增加。氧化壓力會誘發發炎反應,且發炎過程會更進一步造成ROS提升與降低細胞的抗氧化能力。在SCA中,第三型脊髓小腦共濟失調症(SCA3)是脊髓小腦共濟失調症中最常見的一型,在台灣所有病例中約佔50%。先前的文獻發現,在SCA3患者橋腦中,出現星狀細胞與微膠細胞活化,顯示發炎過程參與了疾病的致病機制。本研究首先使用小鼠BV-2和人類HMC3微膠細胞(Microglia),評估四種具潛力化合物NC009-1、AM404、VB-037、LM-031的抗發炎能力。在脂多醣(LPS)及γ型干擾素(IFN-γ)活化的小鼠微膠細胞中,四種化合物皆抑制釋放至培養基的一氧化氮(NO)量,顯示具抗發炎活性。在IFN-γ活化的人類微膠細胞中,四種化合物亦皆能抑制釋放至培養基的NO、介白素-1β (IL-1β)、腫瘤壞死因子-α (TNF-α)、介白素-6 (IL-6)量,並降低細胞中CD68的表現量,顯示其抗發炎活性。為了評估上述化合物於PolyQ SCA的治療潛力,建立了可誘導表現SCA3 ATXN3/Q14~75-GFP並以視黃酸(Retinoic acid)誘導神經分化的SH-SY5Y細胞。待測化合物前處理表現ATXN3/Q75-GFP且神經分化的SH-SY5Y細胞,可以促進神經突生長並減少聚集。視黃酸誘導神經分化及表現ATXN3/Q75-GFP的SH-SY5Y細胞,給予來自LPS及IFN-γ活化的小鼠微膠細胞或IFN-γ刺激的人類微膠細胞的制約培養液(Conditioned medium)的發炎刺激後,增加的凋亡蛋白酶1 (Caspase 1)活性與乳酸脫氫酶(LDH)釋放量,可透過前處理NC009-1、AM404、VB-037、LM-031後而緩解。此外,上述ATXN3/Q75-GFP的SH-SY5Y細胞給予人類微膠細胞制約培養液的發炎刺激後,AM404與LM-031可抑制活性氧化物的上升,NC009-1、AM404、LM-031可以提升神經突生長,NC009-1、VB-037、LM-031可減少PolyQ聚集。接著檢測IL-1發炎相關路徑,發現NC009-1可抑制IκBα-NF-κB路徑的活化,AM404可抑制JNK-JUN路徑的活化,VB-037可抑制JNK-JUN及P38-STAT1路徑的活化,LM-031可抑制IκBα-NF-κB及P38-STAT1路徑的活化。此研究提供新的觀點,有助於第三型小腦萎縮症發炎機制的探討。

    Polyglutamine (polyQ)-mediated spinocerebellar ataxias (SCA) are caused by mutant genes with expanded CAG repeats encoding polyQ tracts. The misfolding and aggregation of polyQ proteins result in a gain of toxicity that are central to pathogenesis and a concomitant increase in reactive oxygen species (ROS) levels and cellular toxicity. Inflammation is one of the manifestations of oxidative stress and inflammatory process may further induce ROS and reduce cellular antioxidant capacity. Among SCA, SCA type 3 (SCA3) is the most common diagnosis worldwide, accounting for nearly 50% of all cases in Taiwanese. Increased numbers of reactive astrocytes and microglia have been found in SCA3 pons, suggesting the involvement of inflammatory process in the disease pathogenesis. In this study, the anti-inflammatory potentials of NC009-1, AM404, VB-037, and LM-031 were evaluated firstly by using mouse BV-2 and human HMC3 microglial cells. In lipopolysaccharide (LPS) and interferon-γ (IFN-γ) activated mouse BV-2 cells, all four compounds displayed anti-inflammatory activity by suppressing nitric oxide (NO) production in cultured medium. In IFN-γ-activated human HMC3 cells, the test compounds also displayed anti-inflammatory activity by suppressing NO, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) production in cultured medium and CD68 expression in cells. To assess the therapeutic potentials of test compounds, retinoic acid differentiated human SH-SY5Y cells with inducible ATXN3/Q14~75-GFP expression and polyQ-length dependent aggregation were established, and pretreatment of test compounds promoted neurite outgrowth and reduced polyQ aggragation. In retinoic acid-differentiated ATXN3/Q75-expressing SH-SY5Y cells inflamed with LPS- and IFN-γ-primed BV-2 or IFN-γ-primed HMC3 conditioned medium, increased caspase 1 activity and lactate dehydrogenase (LDH) release were mitigated by the treatment with NC009-1, AM404, VB-037, and LM-031. In addition, AM404 and LM-031 reduced mutant polyQ-associated reactive oxygen species, NC009-1, AM404, and LM-031 promoted neurite outgrowth, and NC009-1, VB-037, and LM-031 reduced polyQ aggregation in ATXN3/Q75 SH-SY5Y cells stimulated with IFN-γ-primed HMC3 conditioned medium. Examination of IL-1β-mediated pathways in inflamed ATXN3/Q75 SH-SY5Y cells revealed that NC009-1 downregulated IκBα-NF-κB pathway, AM404 downregulated JNK-JUN pathway, VB-037 downregulated JNK-JUN and P38-STAT1 pathways, and LM-031 downregulated IκBα-NF-κB and P38-STAT1 pathways. This study offers new viewpoints to explore the mechanisms of inflammation in spinocerebellar ataxia type 3.

    目錄 i 圖表次 v 摘要 vi 英文摘要 viii 壹、緒論 1 一、脊髓小腦共濟失調症 1 二、第三型脊髓小腦共濟失調症 2 三、神經發炎反應 2 四、介白素-1β和介白素-6中介的發炎路徑 4 五、神經發炎與第三型脊髓小腦共濟失調症的關聯 6 六、潛力化合物N009-1、AM404、VB-037、LM-031 7 貳、研究目的 9 參、研究材料與方法 10 一、誘導式SCA3細胞株建立 10 二、細胞培養與繼代 11 三、化合物的里賓斯基五規則、極性表面積及血腦屏障通透性預測 11 四、DPPH自由基清除能力測定 12 五、化合物細胞毒性檢測 12 六、NO釋放量測試 13 七、免疫細胞化學染色 14 八、細胞處理、蛋白配製及西方墨點分析 14 九、酵素免疫分析 17 十、ATXN3/Q14~75-GFP SH-SY5Y神經突生長與聚集分析 18 十一、前處理化合物於ATXN3/Q75-GFP SH-SY5Y的聚集與神經突生長分析 18 十二、發炎性ATXN3/Q75-GFP SH-SY5Y細胞存活率分析 19 十三、發炎性ATXN3/Q75-GFP SH-SY5Y細胞乳酸脫氫酶(LDH)分析 19 十四、發炎性ATXN3/Q75-GFP SH-SY5Y細胞凋亡蛋白酶1(Caspase 1)活性分析 20 十五、前處理化合物於發炎性ATXN3/Q75-GFP SH-SY5Y的聚集與神經突生長分析 20 十六、發炎性ATXN3/Q75-GFP SH-SY5Y細胞活性氧化物分析 21 十七、統計分析 21 肆、結果 22 一、化合物溶解度及里賓斯基五規則/極性表面積/血腦屏障通透性預測 22 二、化合物自由基清除效力分析 23 三、化合物細胞毒性分析 23 四、以LPS及IFN-γ活化BV-2細胞檢測化合物抗發炎效果 24 五、以IFN-γ活化HMC3細胞檢測化合物抗發炎效果 25 六、誘導式ATXN3/Q14~75-GFP SH-SY5Y細胞 26 七、ATXN3/Q14~75-GFP SH-SY5Y細胞聚集與神經突生長分析 27 八、化合物對ATXN3/Q75-GFP SH-SY5Y細胞聚集與神經突生長分析 28 九、化合物對BV-2制約培養液刺激SCA3細胞發炎的神經保護作用 29 十、化合物對HMC3制約培養液刺激SCA3細胞發炎的神經保護作用 30 十一、化合物對HMC3制約培養液刺激SCA3細胞發炎的活性氧化物、具及與神經突生長分析 31 十二、化合物對HMC3制約培養液刺激SCA3細胞發炎神經保護機轉路徑 33 伍、討論 35 一、第三型脊髓小腦萎縮症致病機制與毒性片段假說 35 二、微膠細胞與神經發炎反應 36 三、潛力化合物生物利用性與神經保護效果 40 四、潛力化合物在發炎模式中達神經保護的機轉路徑 42 伍、結論及未來研究方向 45 陸、參考文獻 46 柒、附錄圖表 58

    Ajayi, A., Yu, X., Lindberg, S., Langel, U., & Strom, A. L. (2012). Expanded ataxin-7 cause toxicity by inducing ROS production from NADPH oxidase complexes in a stable inducible Spinocerebellar ataxia type 7 (SCA7) model. BMC Neurosci, 13, 86.
    Albrecht, M., Golatta, M., Wullner, U., & Lengauer, T. (2004). Structural and functional analysis of ataxin-2 and ataxin-3. Eur J Biochem, 271(15), 3155-3170.
    Azevedo, F. A., Carvalho, L. R., Grinberg, L. T., Farfel, J. M., Ferretti, R. E., Leite, R. E., Jacob Filho, W., Lent, R., & Herculano-Houzel, S. (2009). Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol, 513(5), 532-541.
    Babon, J. J., Varghese, L. N., & Nicola, N. A. (2014). Inhibition of IL-6 family cytokines by SOCS3. Semin Immunol, 26(1), 13-19.
    Barber, S. C., Higginbottom, A., Mead, R. J., Barber, S., & Shaw, P. J. (2009). An in vitro screening cascade to identify neuroprotective antioxidants in ALS. Free Radic Biol Med, 46(8), 1127-1138.
    Barnham, K. J., Masters, C. L., & Bush, A. I. (2004). Neurodegenerative diseases and oxidative stress. Nat Rev Drug Discov, 3(3), 205-214.
    Bichelmeier, U., Schmidt, T., Hubener, J., Boy, J., Ruttiger, L., Habig, K., Poths, S., Bonin, M., Knipper, M., Schmidt, W. J., Wilbertz, J., Wolburg, H., Laccone, F., & Riess, O. (2007). Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence. J Neurosci, 27(28), 7418-7428.
    Blasi, E., Barluzzi, R., Bocchini, V., Mazzolla, R., & Bistoni, F. (1990). Immortalization of murine microglial cells by a v-raf / v-myc carrying retrovirus. J Neuroimmunol, 27(2-3), 229-237.
    Block, M. L., & Hong, J. S. (2005). Microglia and inflammation- mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol, 76(2), 77-98.
    Busquets, O., Ettcheto, M., Verdaguer, E., Castro-Torres, R. D., Auladell, C., Beas-Zarate, C., Folch, J., & Camins, A. (2018). JNK1 inhibition by Licochalcone A leads to neuronal protection against excitotoxic insults derived of kainic acid. Neuropharmacology, 131, 440-452.
    Carson, M. J., Doose, J. M., Melchior, B., Schmid, C. D., & Ploix, C. C. (2006). CNS immune privilege: hiding in plain sight. Immunol Rev, 213, 48-65.
    Ceyzeriat, K., Ben Haim, L., Denizot, A., Pommier, D., Matos, M., Guillemaud, O., Palomares, M. A., Abjean, L., Petit, F., Gipchtein, P., Gaillard, M. C., Guillermier, M., Bernier, S., Gaudin, M., Auregan, G., Josephine, C., Dechamps, N., Veran, J., Langlais, V., Cambon, K., Bemelmans, A. P., Baijer, J., Bonvento, G., Dhenain, M., Deleuze, J. F., Oliet, S. H. R., Brouillet, E., Hantraye, P., Carrillo-de Sauvage, M. A., Olaso, R., Panatier, A., & Escartin, C. (2018). Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer's disease. Acta Neuropathol Commun, 6(1), 104.
    Chang, K. H., Chen, W. L., Lee, L. C., Lin, C. H., Kung, P. J., Lin, T. H., Wu, Y. C., Wu, Y. R., Chen, Y. C., Lee-Chen, G. J., & Chen, C. M. (2013). Aqueous extract of Paeonia lactiflora and paeoniflorin as aggregation reducers targeting chaperones in cell models of spinocerebellar ataxia 3. Evid Based Complement Alternat Med, 2013, 471659.
    Chen, C. M., Chen, W. L., Hung, C. T., Lin, T. H., Chao, C. Y., Lin, C. H., Wu, Y. R., Chang, K. H., Yao, C. F., Lee-Chen, G. J., Su, M. T., & Hsieh-Li, H. M. (2018). The indole compound NC009-1 inhibits aggregation and promotes neurite outgrowth through enhancement of HSPB1 in SCA17 cells and ameliorates the behavioral deficits in SCA17 mice. Neurotoxicology, 67, 259-269.
    Chen, Y. C., Chiu, Y. J., Lin, C. H., Hsu, W. C., Wu, J. L., Huang, C. H., Lin, C. W., Yao, C. F., Huang, H. J., Lo, Y. S., Chen, C. M., Wu, Y. R., Chang, K. H., Lee-Chen, G. J., & Mei Hsieh-Li, H. (2019). Indole compound NC009-1 augments APOE and TRKA in Alzheimer's disease cell and mouse models for neuroprotection and cognitive improvement. J Alzheimers Dis, 67(2), 737-756.
    Chiu, Y. J., Hsieh, Y. H., Lin, T. H., Lee, G. C., Hsieh-Li, H. M., Sun, Y. C., Chen, C. M., Chang, K. H., & Lee-Chen, G. J. (2019). Novel compound VB-037 inhibits Aβ aggregation and promotes neurite outgrowth through enhancement of HSP27 and reduction of P38 and JNK-mediated inflammation in cell models for Alzheimer's disease. Neurochem Int, 125, 175-186.
    Chou, A. H., Yeh, T. H., Ouyang, P., Chen, Y. L., Chen, S. Y., & Wang, H. L. (2008). Polyglutamine-expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulation. Neurobiol Dis, 31(1), 89-101.
    Colton, C. A. (2009). Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol, 4(4), 399-418.
    Costa, B., Siniscalco, D., Trovato, A. E., Comelli, F., Sotgiu, M. L., Colleoni, M., Maione, S., Rossi, F., & Giagnoni, G. (2006). AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain. Br J Pharmacol, 148(7), 1022-1032.
    Davis, R. J. (2000). Signal transduction by the JNK group of MAP kinases. Cell, 103(2), 239-252.
    de Zoete, M. R., Palm, N. W., Zhu, S., & Flavell, R. A. (2014). Inflammasomes. Cold Spring Harb Perspect Biol, 6(12), a016287.
    Dinarello, C. A. (1999). Interleukin-18. Methods, 19(1), 121-132.
    Evert, B. O., Vogt, I. R., Kindermann, C., Ozimek, L., de Vos, R. A. I., Brunt, E. R. P., Schmitt, I., Klockgether, T., & Wüllner, U. (2001). Inflammatory genes are upregulated in expanded ataxin-3-expressing cell lines and spinocerebellar ataxia type 3 brains. J Neurosci, 21(15), 5389-5396.
    Evert, B. O., Vogt, I. R., Vieira-Saecker, A. M., Ozimek, L., de Vos, R. A. I., Brunt, E. R. P., Klockgether, T., & Wüllner, U. (2003). Gene expression profiling in ataxin-3 expressing cell lines reveals distinct effects of normal and mutant ataxin-3. J Neuropathol Exp Neurol, 62(10), 1006-1018.
    Fardghassemi, Y., Tauffenberger, A., Gosselin, S., & Parker, J. A. (2017). Rescue of ATXN3 neuronal toxicity in Caenorhabditis elegans by chemical modification of endoplasmic reticulum stress. Dis Model Mech, 10(12), 1465-1480.
    Franchi, L., Eigenbrod, T., Munoz-Planillo, R., & Nunez, G. (2009). The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol, 10(3), 241-247.
    Furusawa, J.-i., Funakoshi-Tago, M., Mashino, T., Tago, K., Inoue, H., Sonoda, Y., & Kasahara, T. (2009). Glycyrrhiza inflata-derived chalcones, Licochalcone A, Licochalcone B and Licochalcone D, inhibit phosphorylation of NF-κB p65 in LPS signaling pathway. Int Immunopharmacol, 9(4), 499-507.
    Gangwani, M. R., & Kumar, A. (2015). Multiple protein kinases via activation of transcription factors NF-κB, AP-1 and C/EBP-delta regulate the IL-6/IL-8 production by HIV-1 Vpr in astrocytes. PLoS One, 10(8), e0135633.
    Ghosh, S., & Baltimore, D. (1990). Activation in vitro of NF-κB by phosphorylation of its inhibitor IκB. Nature, 344(6267), 678-682.
    Giocondo, F., & Curcio, G. (2018). Spinocerebellar ataxia: a critical review of cognitive and socio-cognitive deficits. Int J Neurosci, 128(2), 182-191.
    Goti, D., Katzen, S. M., Mez, J., Kurtis, N., Kiluk, J., Ben-Haiem, L., Jenkins, N. A., Copeland, N. G., Kakizuka, A., Sharp, A. H., Ross, C. A., Mouton, P. R., & Colomer, V. (2004). A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration. J Neurosci, 24(45), 10266-10279.
    Haacke, A., Broadley, S. A., Boteva, R., Tzvetkov, N., Hartl, F. U., & Breuer, P. (2006). Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3. Hum Mol Genet, 15(4), 555-568.
    Hain, E. G., Sparenberg, M., Rasinska, J., Klein, C., Akyuz, L., & Steiner, B. (2018). Indomethacin promotes survival of new neurons in the adult murine hippocampus accompanied by anti-inflammatory effects following MPTP-induced dopamine depletion. J Neuroinflammation, 15(1), 162.
    Harry, G. J., & Kraft, A. D. (2012). Microglia in the developing brain: a potential target with lifetime effects. Neurotoxicology, 33(2), 191-206.
    Harton, J. A., Linhoff, M. W., Zhang, J., & Ting, J. P. (2002). Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains. J Immunol, 169(8), 4088-4093.
    Havel, L. S., Li, S., & Li, X. J. (2009). Nuclear accumulation of polyglutamine disease proteins and neuropathology. Mol Brain, 2, 21.
    Heinrich, P. C., Behrmann, I., Muller-Newen, G., Schaper, F., & Graeve, L. (1998). Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J, 334(Pt 2), 297-314.
    Hochstrasser, T., Hohsfield, L. A., Sperner-Unterweger, B., & Humpel, C. (2013). β-Amyloid induced effects on cholinergic, serotonergic, and dopaminergic neurons is differentially counteracted by anti-inflammatory drugs. J Neurosci Res, 91(1), 83-94.
    Hsieh, J., Liu, J. W., Harn, H. J., Hsueh, K. W., Rajamani, K., Deng, Y. C., Chia, C. M., Shyu, W. C., Lin, S. Z., & Chiou, T. W. (2017). Human olfactory ensheathing cell transplantation improves motor function in a mouse model of type 3 spinocerebellar ataxia. Cell Transplant, 26(10), 1611-1621.
    Hsu, J. Y., Jhang, Y. L., Cheng, P. H., Chang, Y. F., Mao, S. H., Yang, H. I., Lin, C. W., Chen, C. M., & Yang, S. H. (2017). The truncated C-terminal fragment of mutant ATXN3 disrupts mitochondria dynamics in spinocerebellar ataxia type 3 models. Front Mol Neurosci, 10, 196.
    Hsu, L. J., Sagara, Y., Arroyo, A., Rockenstein, E., Sisk, A., Mallory, M., Wong, J., Takenouchi, T., Hashimoto, M., & Masliah, E. (2000). α-Synuclein promotes mitochondrial deficit and oxidative stress. Am J Pathol, 157(2), 401-410.
    Huang, H. J., Chen, S. L., Huang, H. Y., Sun, Y. C., Lee, G. C., Lee-Chen, G. J., Hsieh-Li, H. M., & Su, M. T. (2019). Chronic low dose of AM404 ameliorates the cognitive impairment and pathological features in hyperglycemic 3xTg-AD mice. Psychopharmacology (Berl), 236(2), 763-773.
    Huang, W., Li, Z., Zhao, L., & Zhao, W. (2017). Simvastatin ameliorate memory deficits and inflammation in clinical and mouse model of Alzheimer's disease via modulating the expression of miR-106b. Biomed Pharmacother, 92, 46-57.
    Hubener, J., Casadei, N., Teismann, P., Seeliger, M. W., Bjorkqvist, M., von Horsten, S., Riess, O., & Nguyen, H. P. (2012). Automated behavioral phenotyping reveals presymptomatic alterations in a SCA3 genetrap mouse model. J Genet Genomics, 39(6), 287-299.
    Huxford, T., & Ghosh, G. (2009). A structural guide to proteins of the NF-κB signaling module. Cold Spring Harb Perspect Biol, 1(3), a000075.
    Huxford, T., Huang, D.-B., Malek, S., & Ghosh, G. (1998). The crystal structure of the IκBα/NF-κB complex reveals mechanisms of NF-κB inactivation. Cell, 95(6), 759-770.
    Ii, M., Sunamoto, M., Ohnishi, K., & Ichimori, Y. (1996). β-Amyloid protein-dependent nitric oxide production from microglial cells and neurotoxicity. Brain Res, 720(1-2), 93-100.
    Islam, M. T. (2017). Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders. Neurol Res, 39(1), 73-82.
    Jana, N. R., & Nukina, N. (2004). Misfolding promotes the ubiquitination of polyglutamine-expanded ataxin-3, the defective gene product in SCA3/MJD. Neurotoxicity Res, 6(7-8), 523-533.
    Janabi, N., Peudenier, S., Héron, B., Ng, K. H., & Tardieu, M. (1995). Establishment of human microglial cell lines after transfection of primary cultures of embryonic microglial cells with the SV40 large T antigen. Neurosci Lett, 195(2), 105-108.
    Jope, R. S., Yuskaitis, C. J., & Beurel, E. (2007). Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. Neurochem Res, 32(4-5), 577-595.
    Kaushal, V., Dye, R., Pakavathkumar, P., Foveau, B., Flores, J., Hyman, B., Ghetti, B., Koller, B. H., & LeBlanc, A. C. (2015). Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-b production and axonal degeneration-associated Caspase-6 activation. Cell Death Differ, 22(10), 1676-1686.
    Kawaguchi, Y., Okamoto, T., Taniwaki, M., Aizawa, M., Inoue, M., Katayama, S., Kawakami, H., Nakamura, S., Nishimura, M., Akiguchi, I., & et al. (1994). CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet, 8(3), 221-228.
    Kempuraj, D., Thangavel, R., Yang, E., Pattani, S., Zaheer, S., Santillan, D. A., Santillan, M. K., & Zaheer, A. (2015). Dopaminergic toxin 1-methyl-4-phenylpyridinium, proteins α-synuclein and glia maturation factor activate mast cells and release inflammatory mediators. PLoS One, 10(8), e0135776.
    Khoshnan, A., Ko, J., Watkin, E. E., Paige, L. A., Reinhart, P. H., & Patterson, P. H. (2004). Activation of the IκB kinase complex and nuclear factor-κB contributes to mutant huntingtin neurotoxicity. J Neurosci, 24(37), 7999-8008.
    Kontogiorgis, C. A., Xu, Y., Hadjipavlou-Litina, D., & Luo, Y. (2007). Coumarin derivatives protection against ROS production in cellular models of Aβ toxicities. Free Radic Res, 41(10), 1168-1180.
    Kostura, M. J., Tocci, M. J., Limjuco, G., Chin, J., Cameron, P., Hillman, A. G., Chartrain, N. A., & Schmidt, J. A. (1989). Identification of a monocyte specific pre-interleukin 1β convertase activity. Proc Natl Acad Sci U S A, 86(14), 5227-5231.
    Lee, L. C., Chen, C. M., Wang, H. C., Hsieh, H. H., Chiu, I. S., Su, M. T., Hsieh-Li, H. M., Wu, C. H., Lee, G. C., Lee-Chen, G. J., & Lin, J. Y. (2012). Role of the CCAAT-binding protein NFY in SCA17 pathogenesis. PLoS One, 7(4), e35302.
    Lee, S. Y., Chiu, Y. J., Yang, S. M., Chen, C. M., Huang, C. C., Lee-Chen, G. J., Lin, W., & Chang, K. H. (2018). Novel synthetic chalcone-coumarin hybrid for Aβ aggregation reduction, antioxidation, and neuroprotection. CNS Neurosci Ther, 24(12), 1286-1298.
    Li, B., Bedard, K., Sorce, S., Hinz, B., Dubois-Dauphin, M., & Krause, K. H. (2009). NOX4 expression in human microglia leads to constitutive generation of reactive oxygen species and to constitutive IL-6 expression. J Innate Immun, 1(6), 570-581.
    Li, X., Liu, H., Fischhaber, P. L., & Tang, T. S. (2015). Toward therapeutic targets for SCA3: Insight into the role of Machado-Joseph disease protein ataxin-3 in misfolded proteins clearance. Prog Neurobiol, 132, 34-58.
    Lin, C.-H., Hsieh, Y.-S., Wu, Y.-R., Hsu, C.-J., Chen, H.-C., Huang, W.-H., Chang, K.-H., Hsieh-Li, H. M., Su, M.-T., Sun, Y.-C., Lee, G.-C., & Lee-Chen, G.-J. (2016). Identifying GSK-3β kinase inhibitors of Alzheimer's disease: Virtual screening, enzyme, and cell assays. Eur J Pharm Sci, 89, 11-19.
    Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1. Adv Drug Deliv Rev, 46(1-3), 3-26.
    Liu, C. M., Sun, Y. Z., Sun, J. M., Ma, J. Q., & Cheng, C. (2012). Protective role of quercetin against lead-induced inflammatory response in rat kidney through the ROS-mediated MAPKs and NF-κB pathway. Biochim Biophys Acta, 1820(10), 1693-1703.
    Liu, H., Wang, L., Lv, M., Pei, R., Li, P., Pei, Z., Wang, Y., Su, W., & Xie, X. Q. (2014). AlzPlatform: an Alzheimer's disease domain-specific chemogenomics knowledgebase for polypharmacology and target identification research. J Chem Inf Model, 54(4), 1050-1060.
    Lu, A., Magupalli, V. G., Ruan, J., Yin, Q., Atianand, M. K., Vos, M. R., Schroder, G. F., Fitzgerald, K. A., Wu, H., & Egelman, E. H. (2014). Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell, 156(6), 1193-1206.
    Lu, A., & Wu, H. (2015). Structural mechanisms of inflammasome assembly. FEBS J, 282(3), 435-444.
    Lu, J. M., Lin, P. H., Yao, Q., & Chen, C. (2010). Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems. J Cell Mol Med, 14(4), 840-860.
    Lukacs, M., Warfvinge, K., Kruse, L. S., Tajti, J., Fulop, F., Toldi, J., Vecsei, L., & Edvinsson, L. (2016). KYNA analogue SZR72 modifies CFA-induced dural inflammation- regarding expression of pERK1/2 and IL-1β in the rat trigeminal ganglion. J Headache Pain, 17(1), 64.
    Mandi, Y., & Vecsei, L. (2012). The kynurenine system and immunoregulation. J Neural Transm (Vienna), 119(2), 197-209.
    Manoharan, S., Guillemin, G. J., Abiramasundari, R. S., Essa, M. M., Akbar, M., & Akbar, M. D. (2016). The role of reactive oxygen species in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntington's disease: A mini review. Oxid Med Cell Longev, 2016, 8590578.
    Mao, J., Yang, J., Zhang, Y., Li, T., Wang, C., Xu, L., Hu, Q., Wang, X., Jiang, S., Nie, X., & Chen, G. (2016). Arsenic trioxide mediates HAPI microglia inflammatory response and subsequent neuron apoptosis through p38/JNK MAPK/STAT3 pathway. Toxicol Appl Pharmacol, 303, 79-89.
    Marella, A., Tanwar, O. P., Saha, R., Ali, M. R., Srivastava, S., Akhter, M., Shaquiquzzaman, M., & Alam, M. M. (2013). Quinoline: A versatile heterocyclic. Saudi Pharm J, 21(1), 1-12.
    Matos, C. A., Almeida, L. P., & Nobrega, C. (2017). Proteolytic cleavage of polyglutamine disease-causing proteins: Revisiting the toxic fragment hypothesis. Curr Pharm Des, 23(5), 753-775.
    Ortega, Z., & Lucas, J. J. (2014). Ubiquitin-proteasome system involvement in Huntington's disease. Front Mol Neurosci, 7, 77.
    Pajouhesh, H., & Lenz, G. R. (2005). Medicinal chemical properties of successful central nervous system drugs. NeuroRx, 2(4), 541-553.
    Pang, T., Wang, J., Benicky, J., Sanchez-Lemus, E., & Saavedra, J. M. (2012). Telmisartan directly ameliorates the neuronal inflammatory response to IL-1b partly through the JNK/c-Jun and NADPH oxidase pathways. J Neuroinflammation, 9, 102.
    Paulson, H. L. (2009). The spinocerebellar ataxias. J Neuroophthalmol, 29(3), 227-237.
    Pearson, G., Robinson, F., Beers Gibson, T., Xu, B. E., Karandikar, M., Berman, K., & Cobb, M. H. (2001). Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev, 22(2), 153-183.
    Qin, L., Liu, Y., Cooper, C., Liu, B., Wilson, B., & Hong, J. S. (2002). Microglia enhance β-amyloid peptide-induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species. J Neurochem, 83(4), 973-983.
    Rahaman, S. O., Harbor, P. C., Chernova, O., Barnett, G. H., Vogelbaum, M. A., & Haque, S. J. (2002). Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene, 21(55), 8404-8413.
    Ramanan, S., Kooshki, M., Zhao, W., Hsu, F. C., & Robbins, M. E. (2008). PPARa ligands inhibit radiation-induced microglial inflammatory responses by negatively regulating NF-κB and AP-1 pathways. Free Radic Biol Med, 45(12), 1695-1704.
    Rhee, S. H., Jones, B. W., Toshchakov, V., Vogel, S. N., & Fenton, M. J. (2003). Toll-like receptors 2 and 4 activate STAT1 serine phosphorylation by distinct mechanisms in macrophages. J Biol Chem, 278(25), 22506-22512.
    Rogers, J., Kirby, L. C., Hempelman, S. R., Berry, D. L., McGeer, P. L., Kaszniak, A. W., Zalinski, J., Cofield, M., Mansukhani, L., Willson, P., & Kogan, F. (1993). Clinical trial of indomethacin in Alzheimer's disease. Neurology, 43(8), 1609-1609.
    Rub, U., Schols, L., Paulson, H., Auburger, G., Kermer, P., Jen, J. C., Seidel, K., Korf, H. W., & Deller, T. (2013). Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7. Prog Neurobiol, 104, 38-66.
    Saliba, S. W., Marcotegui, A. R., Fortwängler, E., Ditrich, J., Perazzo, J. C., Muñoz, E., de Oliveira, A. C. P., & Fiebich, B. L. (2017). AM404, paracetamol metabolite, prevents prostaglandin synthesis in activated microglia by inhibiting COX activity. J Neuroinflammation, 14(1).
    Schöls, L., Bauer, P., Schmidt, T., Schulte, T., & Riess, O. (2004). Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol, 3(5), 291-304.
    Schain, M., & Kreisl, W. C. (2017). Neuroinflammation in neurodegenerative disorders-a review. Curr Neurol Neurosci Rep, 17(3), 25.
    Scheiblich, H., Roloff, F., Singh, V., Stangel, M., Stern, M., & Bicker, G. (2014). Nitric oxide/cyclic GMP signaling regulates motility of a microglial cell line and primary microglia in vitro. Brain Res, 1564, 9-21.
    Schieber, M., & Chandel, N. S. (2014). ROS function in redox signaling and oxidative stress. Curr Biol, 24(10), R453-462.
    Schmidt, T., Landwehrmeyer, G. B., Schmitt, I., Trottier, Y., Auburger, G., Laccone, F., Klockgether, T., Völpel, M., Epplen, J. T., Schöls, L., & Riess, O. (1998). An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients. Brain Pathol, 8(4), 669-679.
    Simoes, A. T., Goncalves, N., Koeppen, A., Deglon, N., Kugler, S., Duarte, C. B., & Pereira de Almeida, L. (2012). Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado-Joseph disease. Brain, 135(Pt 8), 2428-2439.
    Sriram, K., Benkovic, S. A., Hebert, M. A., Miller, D. B., & O'Callaghan, J. P. (2004). Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6 -tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo? J Biol Chem, 279(19), 19936-19947.
    Stéphan, A., Laroche, S., & Davis, S. (2003). Learning deficits and dysfunctional synaptic plasticity induced by aggregated amyloid deposits in the dentate gyrus are rescued by chronic treatment with indomethacin. Eur J Neurosci, 17(9), 1921-1927.
    Sun, L., Li, Y., Jia, X., Wang, Q., Li, Y., Hu, M., Tian, L., Yang, J., Xing, W., Zhang, W., Wang, J., Xu, H., Wang, L., Zhang, D., & Ren, H. (2017). Neuroprotection by IFN-γ via astrocyte-secreted IL-6 in acute neuroinflammation. Oncotarget, 8(25), 40065-40078.
    Sun, Y. M., Lu, C., & Wu, Z. Y. (2016). Spinocerebellar ataxia: relationship between phenotype and genotype - a review. Clin Genet, 90(4), 305-314.
    Tanaka, T., Narazaki, M., & Kishimoto, T. (2014). IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol, 6(10), a016295.
    Tang, Y., Li, T., Li, J., Yang, J., Liu, H., Zhang, X. J., & Le, W. (2014). Jmjd3 is essential for the epigenetic modulation of microglia phenotypes in the immune pathogenesis of Parkinson's disease. Cell Death Differ, 21(3), 369-380.
    Tao, X., Li, N., Liu, F., Hu, Y., Liu, J., & Zhang, Y. M. (2018). In vitro examination of microglia-neuron crosstalk with BV2 cells, and primary cultures of glia and hypothalamic neurons. Heliyon, 4(8), e00730.
    Tugal, D., Liao, X., & Jain, M. K. (2013). Transcriptional control of macrophage polarization. Arterioscler Thromb Vasc Biol, 33(6), 1135-1144.
    Van Der Putten, C., Kuipers, H. F., Zuiderwijk-Sick, E. A., Van Straalen, L., Kondova, I., Van Den Elsen, P. J., & Bajramovic, J. J. (2012). Statins amplify TLR-induced responses in microglia via inhibition of cholesterol biosynthesis. Glia, 60(1), 43-52.
    Velagapudi, R., Baco, G., Khela, S., Okorji, U., & Olajide, O. (2016). Pomegranate inhibits neuroinflammation and amyloidogenesis in IL-1β-stimulated SK-N-SH cells. Eur J Nutr, 55(4), 1653-1660.
    Wang, J., & Campbell, I. L. (2002). Cytokine signaling in the brain: putting a SOCS in it? J Neurosci Res, 67(4), 423-427.
    Wang, S., Yang, H., Yu, L., Jin, J., Qian, L., Zhao, H., Xu, Y., & Zhu, X. (2014). Oridonin attenuates Aβ1–42-induced neuroinflammation and inhibits NF-κB pathway. PLoS One, 9(8), e104745.
    Wang, X. L., Qiao, C. M., Liu, J. O., & Li, C. Y. (2017). Inhibition of the SOCS1-JAK2-STAT3 signaling pathway confers neuroprotection in rats with ischemic stroke. Cell Physiol Biochem, 44(1), 85-98.
    Wu, X., Kosaraju, J., & Tam, K. Y. (2018). Anti-neuroinflammatory effects of SLOH in Aβ-induced BV-2 microglial cells and 3xTg-AD mice involve the inhibition of GSK-3b. Neurosci Lett, 687, 207-215.
    Wu, Y. R., Lin, H. Y., Chen, C. M., Gwinn-Hardy, K., Ro, L. S., Wang, Y. C., Li, S. H., Hwang, J. C., Fang, K., Hsieh-Li, H. M., Li, M. L., Tung, L. C., Su, M. T., Lu, K. T., & Lee-Chen, G. J. (2004). Genetic testing in spinocerebellar ataxia in Taiwan: expansions of trinucleotide repeats in SCA8 and SCA17 are associated with typical Parkinson's disease. Clin Genet, 65(3), 209-214.
    Yang, C. M., Lin, C. C., Lee, I. T., Lin, Y. H., Yang, C. M., Chen, W. J., Jou, M. J., & Hsiao, L. D. (2012). Japanese encephalitis virus induces matrix metalloproteinase-9 expression via a ROS/c-Src/PDGFR/PI3K/Akt/MAPKs-dependent AP-1 pathway in rat brain astrocytes. J Neuroinflammation, 9, 12.
    Yu, Y. C., Kuo, C. L., Cheng, W. L., Liu, C. S., & Hsieh, M. (2009). Decreased antioxidant enzyme activity and increased mitochondrial DNA damage in cellular models of Machado-Joseph disease. J Neurosci Res, 87(8), 1884-1891.
    Zarubin, T., & Han, J. (2005). Activation and signaling of the p38 MAP kinase pathway. Cell Res, 15(1), 11-18.
    Zuk, M., Kulma, A., Dyminska, L., Szoltysek, K., Prescha, A., Hanuza, J., & Szopa, J. (2011). Flavonoid engineering of flax potentiate its biotechnological application. BMC Biotechnol, 11, 10.

    無法下載圖示 電子全文延後公開
    2024/12/31
    QR CODE