發(fā)布時(shí)間：2018-06-24 20:12

  本文選題：火麻仁木脂素酰胺 + Grossamide　； 參考：《山東大學(xué)》2017年碩士論文

【摘要】：目前,神經(jīng)退行性疾病(阿爾茨海默病,帕金森病和多發(fā)性硬化等)的發(fā)病率越來(lái)越高并趨于低齡化。這些疾病的發(fā)生、發(fā)展與氧化損傷、免疫炎癥、線粒體功能性障礙、興奮性毒素和細(xì)胞凋亡等機(jī)制有關(guān)。研究發(fā)現(xiàn)在神經(jīng)退行性疾病的發(fā)生、發(fā)展過(guò)程中,小膠質(zhì)細(xì)胞介導(dǎo)的炎癥相關(guān)反應(yīng)起著非常重要作用。細(xì)胞性毒素、化學(xué)、物理刺激等均會(huì)激活小膠質(zhì)細(xì)胞,并釋放大量的炎癥因子,加劇炎癥反應(yīng)。小膠質(zhì)細(xì)胞誘導(dǎo)神經(jīng)炎癥的發(fā)生并活化很多相關(guān)信號(hào)通路,比如:Toll樣受體,JAK/STAT,NF-κB和MAPK等。其中NF-κB是介導(dǎo)炎癥發(fā)生的重要信號(hào)通路,NF-κB的激活會(huì)誘導(dǎo)產(chǎn)生大量的炎癥細(xì)胞因子,炎癥因子反過(guò)來(lái)刺激細(xì)胞,使細(xì)胞發(fā)生持續(xù)的激活,進(jìn)而控制大量細(xì)胞因子的基因表達(dá)。在小膠質(zhì)細(xì)胞激活過(guò)程中,NF-κB會(huì)與其他炎癥相關(guān)通路共同作用,調(diào)節(jié)炎癥反應(yīng)。所以,發(fā)現(xiàn)有效的控制NF-κB信號(hào)通路活化的化合物將有望成為神經(jīng)退行性相關(guān)疾病治療的潛在方法�；鹇槿侍崛∥镌谏窠�(jīng)保護(hù)方面具有較好的活性,本課題組前期對(duì)火麻仁進(jìn)行了化學(xué)成分研究,獲得了一系列木脂素酰胺類化合物。本論文通過(guò)建立脂多糖(LPS)刺激BV2小膠質(zhì)細(xì)胞的神經(jīng)炎癥模型,對(duì)這些化合物進(jìn)行了抗炎活性篩選,并對(duì)篩選出的活性化合物grossamide、cannabisin F是否抑制LPS引起的NF-κB信號(hào)通路的激活進(jìn)行研究,以發(fā)現(xiàn)其通過(guò)NF-κB信號(hào)通路干預(yù)來(lái)治療神經(jīng)炎癥相關(guān)疾病的潛力。研究結(jié)果表明grossamide表現(xiàn)出潛在的抗炎活性。ELISA及qRT-PCR結(jié)果顯示grossamide可以抑制LPS誘導(dǎo)的BV2細(xì)胞的炎癥因子IL-6和TNF-α的表達(dá)。Western blot和免疫熒光等檢測(cè)結(jié)果顯示grossamide可以抑制IκBα及NF-κBp65蛋白的磷酸化,阻止NF-κBp65表達(dá)入核,同時(shí)阻止了 NF-κB上游蛋白TLR4及MyD88的表達(dá)。說(shuō)明grossamide可以通過(guò)抑制TLR4介導(dǎo)的NF-κB的信號(hào)通路起到保護(hù)小膠質(zhì)細(xì)胞的作用。研究結(jié)果表明cannabisin F同樣表現(xiàn)出抗炎能力。細(xì)胞內(nèi)活性氧檢測(cè)結(jié)果顯示cannabisin F可以抑制BV2細(xì)胞產(chǎn)生ROS。Western blot結(jié)果顯示cannabisin F可以促進(jìn)SIRT1,Nrf-2及下游蛋白HO-1的表達(dá),同時(shí)可以抑制IκBα及NF-κBp65蛋白的磷酸化表達(dá)。ELISA及RT-PCR的結(jié)果顯示cannabisin F可以抑制LPS刺激BV2細(xì)胞產(chǎn)生的炎癥因子IL-6和TNF-α的表達(dá)。說(shuō)明cannabisin F可通過(guò)激活SIRT1/Nrf-2信號(hào)通路,抑制NF-κB信號(hào)通路起到神經(jīng)保護(hù)作用。
[Abstract]:At present, the incidence of neurodegenerative diseases (Alzheimer's, Parkinson's and multiple sclerosis, etc.) is becoming higher and lower. The occurrence and development of these diseases are related to oxidative damage, immune inflammation, mitochondrial dysfunction, excitatory toxins, and apoptosis. In the course of development, microglia mediated inflammation related reactions play a very important role. Cytotoxin, chemistry, physical stimulation, etc. can activate microglia and release a large number of inflammatory factors to aggravate the inflammatory response. Microglia induces neuroinflammation and activates many related signaling pathways, such as Toll like receptor, JAK /STAT, NF- kappa B and MAPK, in which NF- kappa B is an important signaling pathway to mediate the occurrence of inflammation, the activation of NF- kappa B induces a large number of inflammatory cytokines, which in turn stimulate the cells to enable the cell to continue to activate, and then control the gene expression of a large number of cytokines. In the process of microglia activation, NF- kappa B will be associated with the others. The inflammation related pathway acts together to regulate the inflammatory response. Therefore, the discovery of effective compounds to control the activation of the NF- kappa B signaling pathway is expected to be a potential method for the treatment of neurodegenerative diseases. A series of lignan amide compounds were obtained. In this paper, the inflammatory models of BV2 microglia were stimulated by lipopolysaccharide (LPS), and the anti-inflammatory activity of these compounds was screened. The activated compound grossamide, whether cannabisin F inhibited the activation of NF- kappa B signaling pathway caused by LPS, was studied. The potential of the treatment of neuroinflammatory related diseases through the intervention of NF- kappa B signaling pathway is present. The results show that grossamide shows the potential anti-inflammatory activity.ELISA and qRT-PCR results show that grossamide can inhibit the expression of IL-6 and TNF- a of BV2 cells induced by LPS, and the results of.Western blot and immunofluorescence are shown. Amide can inhibit the phosphorylation of I kappa B alpha and NF- kappa Bp65 protein, prevent the expression of NF- kappa Bp65 into nucleus, and prevent the expression of TLR4 and MyD88 of the upstream protein of NF- kappa B. The results of intracellular active oxygen detection showed that cannabisin F could inhibit the production of ROS.Western blot by BV2 cells and that cannabisin F could promote the expression of SIRT1, Nrf-2 and downstream protein HO-1. The expression of inflammatory factors IL-6 and TNF- alpha produced by the cells indicates that cannabisin F can inhibit the neuroprotective effect of the NF- kappa B signaling pathway by activating the SIRT1/Nrf-2 signaling pathway.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R285

【參考文獻(xiàn)】

相關(guān)期刊論文 前10條

1 林珍梅;陳林妹;梁梓敏;夏星;;火麻仁不同提取物對(duì)實(shí)驗(yàn)性Alzheimer's癥小鼠的治療作用[J];中藥藥理與臨床;2016年06期

2 李璐;邵金平;任秀花;臧衛(wèi)東;韓雪萍;;地塞米松抑制谷氨酸誘導(dǎo)的大鼠小膠質(zhì)細(xì)胞活化[J];細(xì)胞與分子免疫學(xué)雜志;2016年05期

3 WANG Pei-Pei;ZHAO Guo-Wei;XIA Wen;HAN En-Ji;XIANG Lan;;A new flavonol C-glycoside and a rare bioactive lignanamide from Piper wallichii Miq. Hand.-Mazz[J];Chinese Journal of Natural Medicines;2014年05期

4 鄺棗園;孫硯輝;孫冬梅;馬Z，

本文編號(hào)：2062777