Please use this identifier to cite or link to this item:
https://ah.lib.nccu.edu.tw/handle/140.119/78090| 題名: | 雙酚合成物抑制氧化壓力及加強神經生長因子誘導神經突生長 The novel biphenol compounds inhibit oxidative stress and enhance nerve growth factor (NGF)-induced neurite outgrowth |
作者: | 林芊瑜 | 貢獻者: | 詹銘煥 林芊瑜 |
關鍵詞: | 雙酚化合物 腎上腺髓質嗜鉻細胞瘤 神經保護 神經突生長 細胞外信號調節激酶(Erk1/2) 訊息傳遞轉錄活化基因-3(STAT3) |
日期: | 2015 | 上傳時間: | 1-Sep-2015 | 摘要: | 人類隨著年齡增長後中樞神經系統的修補及再生能力逐漸下降，一旦神經系統受到傷害，是很嚴重的問題。因此，引導或促進神經細胞生長甚至再生的方法，中樞神經受損患者將獲得更有效的治療。先前已有文獻指出由植物厚朴萃取的天然化合物─和厚朴酚，具有抗氧化、抗腫瘤、抗發炎、神經保護與滋養的作用。在不同疾病模式的囓齒動物實驗，如帕金森氏症、阿茲海默症、癌症與腦缺血疾病等，和厚朴酚皆具有預防疾病或減緩症狀的效果。本篇研究使用和厚朴酚之衍生物─新合成雙酚化合物(MH102、MH103、MH104、MH106、MH107與MH111)，並探討對於神經細胞的保護與滋養作用。透過腎上腺髓質嗜鉻細胞瘤 PC12 細胞預先處理新合成雙酚化合物，並以過氧化氫(H2O2)使細胞產生氧化壓力，使用活性氧檢測試驗(DCFH-DA assay)偵測細胞內活性氧(reactive oxygen species, ROS)的含量。實驗結果顯示，預先處理較高濃度(3-10μM)的新合成雙酚化合物顯著降低過氧化氫所產生的氧化壓力。另以H2O2誘導PC12細胞死亡，並使用MTT試驗法，觀測新合成雙酚化合物對於細胞存活的影響。結果顯示新合成雙酚化合物顯著減少H2O2造成的細胞死亡。於神經滋養實驗，發現新合成雙酚化合物無法直接誘導PC12細胞的神經突生長。因此，使用神經滋養因子(nerve growth factor, NGF)誘導PC12細胞神經突生長，發現新合成雙酚化合物在低濃度(0.1-0.3μM)顯著加強神經突生長。然而雙酚化合物加強NGF誘導神經突生長之機制，並非透過活化細胞外信號調節激酶 (extracellular-signal-regulated kinases, Erk1/2)與訊息傳遞轉錄活化基因-3 (signal transducer and activator of transcription 3, STAT3)，Erk1/2的活化在短時間內(5至10分鐘) 反而減少，STAT3的活化則沒有差異。由此推論，新合成雙酚化合物的保護作用是透過減少ROS的產生，並可以加強NGF對於PC12細胞的神經突生長，但不是透過Erk1/2或STAT3路徑所致。 | 參考文獻: | Akira S, Nishio Y, Inoue M, Wang X-J, We S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T (1994) Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77:63-71.\nAi J, Wang X, Nielsen M (2001) Honokiol and magnolol selectively interact with GABAA receptor subtypes in vitro. Pharmacology 63:34-41.\nAllen SJ, Dawbarn D (2006) Clinical relevance of the neurotrophins and their receptors. Clinical science (London, England : 1979) 110:175-191.\nAloe L, Bracci-Laudiero L, Bonini S, Manni L (1997) The expanding role of nerve growth factor: from neurotrophic activity to immunologic diseases. Allergy 52:883-894.\nAvraham R, Yarden Y (2011) Feedback regulation of EGFR signalling: decision making by early and delayed loops. Nature reviews Molecular cell biology 12:104-117.\nBai X, Cerimele F, Ushio-Fukai M, Waqas M, Campbell PM, Govindarajan B, Der CJ, Battle T, Frank DA, Ye K (2003) Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo. Journal of Biological Chemistry 278:35501-35507.\nBroderick J, Brott T, Kothari R, Miller R, Khoury J, Pancioli A, Gebel J, Mills D, Minneci L, Shukla R (1998) The Greater Cincinnati/Northern Kentucky Stroke Study Preliminary first-ever and total incidence rates of stroke among blacks. Stroke 29:415-421.\nBureau G, Longpré F, Martinoli MG (2008) Resveratrol and quercetin, two natural polyphenols, reduce apoptotic neuronal cell death induced by neuroinflammation. Journal of neuroscience research 86:403-410.\nChao LK, Liao PC, Ho CL, Wang EI, Chuang CC, Chiu HW, Hung LB, Hua KF (2010) Anti-inflammatory bioactivities of honokiol through inhibition of protein kinase C, mitogen-activated protein kinase, and the NF-kappaB pathway to reduce LPS-induced TNFalpha and NO expression. Journal of agricultural and food chemistry 58:3472-3478.\nChao MV, Rajagopal R, Lee FS (2006) Neurotrophin signalling in health and disease. Clinical science (London, England : 1979) 110:167-173.\nChen CM, Liu SH, Lin-Shiau SY (2007) Honokiol, a neuroprotectant against mouse cerebral ischaemia, mediated by preserving Na+, K+-ATPase activity and mitochondrial functions. Basic & clinical pharmacology & toxicology 101:108-116.\nChuang DY, Chan M-H, Zong Y, Sheng W, He Y, Jiang JH, Simonyi A, Gu Z, Fritsche KL, Cui J (2013) Magnolia polyphenols attenuate oxidative and inflammatory responses in neurons and microglial cells. J Neuroinflammation 10:15.\nDikalov S, Losik T, Arbiser JL (2008) Honokiol is a potent scavenger of superoxide and peroxyl radicals. Biochemical pharmacology 76:589-596.\nDreyfus CF (1989) Effects of nerve growth factor on cholinergic brain neurons. Trends in pharmacological sciences 10:145-149.\nEbendal T (1992) Function and evolution in the NGF family and its receptors. Journal of neuroscience research 32:461-470.\nFried LE, Arbiser JL (2009) Honokiol, a multifunctional antiangiogenic and antitumor agent. Antioxidants & redox signaling 11:1139-1148.\nFriedman WJ, Greene LA (1999) Neurotrophin signaling via Trks and p75. Experimental cell research 253:131-142.\nFukuyama Y, Nakade K, Minoshima Y, Yokoyama R, Zhai H, Mitsumoto Y (2002) Neurotrophic activity of honokiol on the cultures of fetal rat cortical neurons. Bioorganic & medicinal chemistry letters 12:1163-1166.\nGreene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proceedings of the National Academy of Sciences of the United States of America 73:2424-2428.\nGuttmacher AE, Collins FS, Nussbaum RL, Ellis CE (2003) Alzheimer`s disease and Parkinson`s disease. New England Journal of Medicine 348:1356-1364.\nHirano T, Ishihara K, Hibi M (2000) Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19:2548-2556.\nHo KY, Tsai CC, Chen CP, Huang JS, Lin CC (2001) Antimicrobial activity of honokiol and magnolol isolated from Magnolia officinalis. Phytotherapy Research 15:139-141.\nHoi CP, Ho YP, Baum L, Chow AHL (2010a) Neuroprotective effect of honokiol and magnolol, compounds from Magnolia officinalis, on beta-amyloid-induced toxicity in PC12 cells. Phytotherapy Research 24:1538-1542.\nHoi CP, Ho YP, Baum L, Chow AH (2010b) Neuroprotective effect of honokiol and magnolol, compounds from Magnolia officinalis, on beta-amyloid-induced toxicity in PC12 cells. Phytotherapy research : PTR 24:1538-1542.\nHou YC, Chao PD, Chen SY (2000) Honokiol and magnolol increased hippocampal acetylcholine release in freely-moving rats. The American journal of Chinese medicine 28:379-384.\nHua H, Chen W, Shen L, Sheng Q, Teng L (2013) Honokiol augments the anti-cancer effects of oxaliplatin in colon cancer cells. Acta biochimica et biophysica Sinica 45:773-779.\nHuang EJ, Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Annual review of biochemistry 72:609-642.\nHwang J-T, Kwon DY, Park OJ, Kim MS (2008) Resveratrol protects ROS-induced cell death by activating AMPK in H9c2 cardiac muscle cells. Genes & nutrition 2:323-326.\nIbáñez C, Cifuentes A, Simó C (2015) Recent Advances and Applications of Metabolomics to Investigate Neurodegenerative Diseases. International Review of Neurobiology.\nIto H, Sun X-L, Watanabe M, Okamoto M, Hatano T (2008) Chlorogenic acid and its metabolite m-coumaric acid evoke neurite outgrowth in hippocampal neuronal cells. Bioscience, biotechnology, and biochemistry 72:885-888.\nKaplan DR, Miller FD (2000) Neurotrophin signal transduction in the nervous system. Current opinion in neurobiology 10:381-391.\nKlesse LJ, Parada LF (1999) Trks: signal transduction and intracellular pathways. Microscopy research and technique 45:210-216.\nKurata M, Suzuki M, Agar NS (1993) Antioxidant systems and erythrocyte life-span in mammals. Comparative biochemistry and physiology B, Comparative biochemistry 106:477-487.\nLee J, Jung E, Park J, Jung K, Lee S, Hong S, Park E, Kim J, Park S, Park D (2005) Anti-inflammatory effects of magnolol and honokiol are mediated through inhibition of the downstream pathway of MEKK-1 in NF-kappaB activation signaling. Planta medica 71:338-343.\nLee SY, Cho JS, Yuk DY, Moon DC, Jung JK, Yoo HS, Lee YM, Han SB, Oh K-W, Hong JT (2009a) Obovatol enhances docetaxel-induced prostate and colon cancer cell death through inactivation of nuclear transcription factor-kappaB. Journal of pharmacological sciences 111:124-136.\nLee YK, Choi IS, Kim YH, Kim KH, Nam SY, Yun YW, Lee MS, Oh KW, Hong JT (2009b) Neurite Outgrowth Effect of 4-O-methylhonokiol by Induction of Neurotrophic Factors Through ERK Activation. Neurochemical Research 34:2251-2260.\nLee YJ, Choi IS, Park MH, Lee YM, Song JK, Kim YH, Kim KH, Hwang DY, Jeong JH, Yun YP, Oh KW, Jung JK, Han SB, Hong JT (2011) 4-O-Methylhonokiol attenuates memory impairment in presenilin 2 mutant mice through reduction of oxidative damage and inactivation of astrocytes and the ERK pathway. Free radical biology & medicine 50:66-77.\nLeonard SS, Xia C, Jiang B-H, Stinefelt B, Klandorf H, Harris GK, Shi X (2003) Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses. Biochemical and biophysical research communications 309:1017-1026.\nLevi-Montalcini R (1987) The nerve growth factor: thirty-five years later. The EMBO journal 6:1145-1154.\nLin YR, Chen HH, Ko CH, Chan MH (2006) Neuroprotective activity of honokiol and magnolol in cerebellar granule cell damage. European journal of pharmacology 537:64-69.\nLiou K-T, Shen Y-C, Chen C-F, Tsao C-M, Tsai S-K (2003) Honokiol protects rat brain from focal cerebral ischemia–reperfusion injury by inhibiting neutrophil infiltration and reactive oxygen species production. Brain research 992:159-166.\nMartinez J, Moreno JJ (2000) Effect of resveratrol, a natural polyphenolic compound, on reactive oxygen species and prostaglandin production. Biochemical pharmacology 59:865-870.\nMatrone C, Ciotti MT, Mercanti D, Marolda R, Calissano P (2008) NGF and BDNF signaling control amyloidogenic route and Aβ production in hippocampal neurons. Proceedings of the National Academy of Sciences 105:13139-13144.\nMatsui N, Takahashi K, Takeichi M, Kuroshita T, Noguchi K, Yamazaki K, Tagashira H, Tsutsui K, Okada H, Kido Y, Yasui Y, Fukuishi N, Fukuyama Y, Akagi M (2009) Magnolol and honokiol prevent learning and memory impairment and cholinergic deficit in SAMP8 mice. Brain Research 1305:108-117.\nMcAllister AK (2001) Neurotrophins and neuronal differentiation in the central nervous system. Cellular and molecular life sciences : CMLS 58:1054-1060.\nMiller FD, Kaplan DR (2001) Neurotrophin signalling pathways regulating neuronal apoptosis. Cellular and molecular life sciences : CMLS 58:1045-1053.\nMiyata Y, Nishida E (1999) Distantly related cousins of MAP kinase: biochemical properties and possible physiological functions. Biochemical and biophysical research communications 266:291-295.\nNg YP, Cheung ZH, Ip NY (2006) STAT3 as a downstream mediator of Trk signaling and functions. Journal of Biological Chemistry 281:15636-15644.\nOgata M, Hoshi M, Shimotohno K, Urano S, Endo T (1997) Antioxidant activity of magnolol, honokiol, and related phenolic compounds. Journal of the American Oil Chemists` Society 74:557-562.\nOlanow C, Tatton W (1999) Etiology and pathogenesis of Parkinson`s disease. Annual review of neuroscience 22:123-144.\nPark Y, Han D-W, Suh H, Ryu G, Hyon S-H, Cho B, Park J-C (2003) Protective effects of green tea polyphenol against reactive oxygen species-induced oxidative stress in cultured rat calvarial osteoblast. Cell biology and toxicology 19:325-337.\nPerron JC, Bixby JL (1999) Distinct neurite outgrowth signaling pathways converge on ERK activation. Molecular and Cellular Neuroscience 13:362-378.\nQuarta S, Baeumer BE, Scherbakov N, Andratsch M, Rose-John S, Dechant G, Bandtlow CE, Kress M (2014) Peripheral nerve regeneration and NGF-dependent neurite outgrowth of adult sensory neurons converge on STAT3 phosphorylation downstream of neuropoietic cytokine receptor gp130. The Journal of neuroscience : the official journal of the Society for Neuroscience 34:13222-13233.\nReichardt LF (2006) Neurotrophin-regulated signalling pathways. Philosophical transactions of the Royal Society of London Series B, Biological sciences 361:1545-1564.\nScherz-Shouval R, Elazar Z (2007) ROS, mitochondria and the regulation of autophagy. Trends in cell biology 17:422-427.\nSchor NF (2005) The p75 neurotrophin receptor in human development and disease. Progress in neurobiology 77:201-214.\nSinet PM, Bresson JL, Couturier J, Laurent C, Prieur M, Rethore MO, Taillemite JL, Toudic D, Jerome H, Lejeune J (1977) [Possible localization of the glutathione reductase (EC 1.6.4.2) on the 8p21 band]. Annales de genetique 20:13-17.\nTse AK, Wan CK, Shen XL, Yang M, Fong WF (2005) Honokiol inhibits TNF-alpha-stimulated NF-kappaB activation and NF-kappaB-regulated gene expression through suppression of IKK activation. Biochem Pharmacol 70:1443-1457.\nVaudry D, Stork P, Lazarovici P, Eiden L (2002) Signaling pathways for PC12 cell differentiation: making the right connections. Science (New York, NY) 296:1648-1649.\nWang X, Duan X, Yang G, Zhang X, Deng L, Zheng H, Deng C, Wen J, Wang N, Peng C, Zhao X, Wei Y, Chen L (2011) Honokiol crosses BBB and BCSFB, and inhibits brain tumor growth in rat 9L intracerebral gliosarcoma model and human U251 xenograft glioma model. PloS one 6:e18490.\nXu HL, Tang W, Du GH, Kokudo N (2011) Targeting apoptosis pathways in cancer with magnolol and honokiol, bioactive constituents of the bark of Magnolia officinalis. Drug discoveries & therapeutics 5:202-210.\nZhai H, Inoue T, Moriyama M, Esumi T, Mitsumoto Y, Fukuyama Y (2005a) Neuroprotective effects of 2, 5-diaryl-3, 4-dimethyltetrahydrofuran neolignans. Biol Pharm Bull 28:289-293.\nZhai H, Nakade K, Oda M, Mitsumoto Y, Akagi M, Sakurai J, Fukuyama Y (2005b) Honokiol-induced neurite outgrowth promotion depends on activation of extracellular signal-regulated kinases (Erk1/2). European Journal of Pharmacology 516:112-117.\nZhou L, Too HP (2011) Mitochondrial localized STAT3 is involved in NGF induced neurite outgrowth. PloS one 6:e21680. | 描述: | 碩士 國立政治大學 神經科學研究所 102754005 |
資料來源: | http://thesis.lib.nccu.edu.tw/record/#G0102754005 | 資料類型: | thesis |
| Appears in Collections: | 學位論文 |
Files in This Item:
| File | Size | Format | |
|---|---|---|---|
| 400501.pdf | 4.22 MB | Adobe PDF2 | View/Open |
Google ScholarTM
Check
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.