發(fā)布時間：2018-05-13 17:09

  本文選題：自身免疫疾病 + 免疫抑制劑��； 參考：《中國科學院大學(中國科學院上海藥物研究所)》2017年碩士論文

【摘要】：銀屑病是一種常見的自身免疫疾病,臨床表現(xiàn)為紅色瘢痕,發(fā)病部位常遍布全身,嚴重影響患者生活1。目前為止銀屑病的發(fā)病機制還不清楚,通常認為是由功能失調(diào)的角質(zhì)細胞、活化的T細胞、固有免疫細胞以及多種炎癥因子共同作用的結果。目前的治療手段主要采取激素治療、免疫抑制劑治療、光療法以及新興的生物制劑療法,但依然面臨易復發(fā)的缺點,所以人們還在不斷的努力尋找新的安全經(jīng)濟有效的治療藥物。青蒿素是從我國傳統(tǒng)中藥青蒿(Artemisia annua L.)中提取的有效成分,在治療治療瘧疾方面有著高效低毒的優(yōu)勢。青蒿素所具備的廣泛的抗炎抗腫瘤和免疫抑制的藥理活性以及安全性,讓它越來越受到科研人員的關注,但它同時也有著水溶性差,口服利用率低下的缺點,這限制了青蒿素的應用范圍。本實驗室對青蒿素進行了一系列結構改造和活性篩選,最終獲得了多種青蒿素衍生物,其中SM934具備水溶性好,毒性低,活性高的優(yōu)勢,故將其作為候選藥物,探索對銀屑病的治療作用。本課題的研究目的是通過體內(nèi)外手段探究青蒿素衍生物SM934對銀屑病的治療作用。體內(nèi)實驗中,通過經(jīng)皮給藥的方式探索SM934對銀屑病鼠尾鱗片模型的治療作用,將BALB/c雌性小鼠作為實驗動物,分別在鼠尾外涂SM934凝膠、維A酸、凝膠基質(zhì)。2次/day,在第14天處死BALB/c小鼠,取距離尾根約2 cm處尾部背側(cè)皮膚,HE染色,于顯微鏡下觀察鱗片表皮是否有顆粒層形成,計算正角化率。結果顯示SM934凝膠能有效地治療鼠尾鱗片模型,促進角質(zhì)形成細胞角質(zhì)化。對于人永生化的角質(zhì)形成細胞(HaCaT細胞),CCK8細胞毒性實驗顯示水溶性青蒿素衍生物SM934對HaCaT細胞毒性較低。在臨床上,銀屑病患者皮損處IL-6、IL-8、K17、S100A8的含量與皮損嚴重程度有一定的正相關關系。ELISA實驗及RT-PCR的實驗表明:TNF-α、IFN-γ共刺激能促進HaCaT細胞分泌細胞因子IL-6。TNF-α、IL-17共刺激能促進HaCaT細胞表達IL-6、IL-8、K17、S100A8、CXCL5等與銀屑病發(fā)病相關的細胞因子。同時SM934能顯著抑制HaCaT細胞表達上述細胞因子,抑制HaCaT細胞參與的炎癥反應。體內(nèi)試驗顯示,SM934能促進角質(zhì)形成細胞正角質(zhì)化,促進顆粒層細胞的形成,體外實驗表明SM934能夠抑制角質(zhì)細胞炎癥反應。說明SM934對于銀屑病的有一定的治療作用,為將來進一步探索青蒿素類衍生物治療銀屑病提供了實驗依據(jù)。
[Abstract]:Psoriasis is a common autoimmune disease, clinical manifestations are red scar, the site of the disease is often spread throughout the body, seriously affecting the life of patients 1. So far, the pathogenesis of psoriasis is not clear. It is generally considered to be the result of the combined action of dysfunctional keratinocytes, activated T cells, innate immune cells and various inflammatory factors. The current treatments include hormone therapy, immunosuppressant therapy, phototherapy and emerging biologics, but they still face the drawback of being prone to relapse. So people are still trying to find new safe, economical and effective treatment drugs. Artemisia annua L. The active components extracted from the drug have the advantage of high efficiency and low toxicity in the treatment of malaria. Artemisinin has a wide range of anti-inflammatory, anti-tumor and immunosuppressive pharmacological activities and safety, making it more and more concerned by researchers, but it also has the shortcomings of poor water solubility and low oral utilization. This limits the application of artemisinin. A series of structural modification and activity screening of artemisinin were carried out in our laboratory, and a variety of artemisinin derivatives were obtained. Among them, SM934 has the advantages of good water solubility, low toxicity and high activity, so it is used as a candidate drug. To explore the therapeutic effect on psoriasis. The aim of this study was to explore the therapeutic effect of artemisinin derivative SM934 on psoriasis in vitro and in vivo. In vivo, the therapeutic effect of SM934 on the tail scales of psoriatic rats was explored by percutaneous administration. The female BALB/c mice were treated with SM934 gel and retinoic acid respectively. On the 14th day, the BALB/c mice were killed on the 14th day. The dorsal tail skin was stained with HE at a distance of about 2 cm from the tail root. The granular layer was observed under the microscope and the positive keratinization rate was calculated. The results showed that SM934 gel could effectively treat rat tail scale model and promote keratinization of keratinocytes. The cytotoxicity of SM934, a water-soluble artemisinin derivative, to HaCaT cells was found to be low in human immortalized keratinocytes. Clinically, In psoriatic patients, there was a positive correlation between the content of IL-6, IL-8, IL-8, S100A8, and the severity of the lesions. Elisa and RT-PCR experiments showed that the co-stimulation of TNF- 偽 and IFN- 緯 promoted the secretion of cytokine IL-6.TNF- 偽 -IL-17 by HaCaT cells, and promoted the expression of IL-6IL-8K17A100A8CXCL5 by HaCaT cells. The cytokines associated with the development of chiff disease. At the same time, SM934 could significantly inhibit the expression of cytokines in HaCaT cells and inhibit the inflammatory response of HaCaT cells. In vivo experiments showed that SM934 could promote the keratinization of keratinocytes and promote the formation of granular layer cells. In vitro, SM934 could inhibit the inflammatory response of keratinocytes. The results suggest that SM934 has a certain therapeutic effect on psoriasis and provides experimental basis for further exploration of artemisinin derivatives in the treatment of psoriasis.
【學位授予單位】：中國科學院大學(中國科學院上海藥物研究所)
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R96

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