本文選題：沙棘多糖 + 撲熱息痛　； 參考：《內蒙古農業(yè)大學》2017年碩士論文

【摘要】：藥物性肝損傷(Drug-induced liver injury,DILI)是由藥物本身及其代謝產(chǎn)物所引發(fā)的肝臟損傷,是引起急性肝衰竭的主要原因。沙棘果被認為在藏醫(yī)和蒙醫(yī)中具有很高的藥用價值,可治療多種疾病,但對于沙棘果多糖提取物(Seabucthorn berry po1ysaccharide,SP)治療 DILI 的研究甚少。本實驗通過模擬撲熱息痛(Acetaminophen,APAP)誘導的小鼠藥物性肝損傷過程,探究沙棘多糖對藥物性肝損傷的保護作用及其機制,為開發(fā)綠色保肝新藥提供科學依據(jù)。C57BL/6雄性小鼠隨機分為六組,即空白對照組(Ctrl),APAP模型組(APAP),N-乙酰半胱氨酸組(NAC),沙棘多糖低劑量組(APAP/SP100),沙棘多糖高劑量組(APAP/SP200),沙棘多糖對照組(SP200),沙棘多糖低、高劑量組及對照組分別以100、200、200mg.kg-1 SP連續(xù)灌胃30天后,腹腔注射撲熱息痛(350mg.kg-1)構建DILI模型,NAC(150mg.kg-1)于建模前1h腹腔注射。16h后處死小鼠,收集血清及肝臟樣本,分別檢測血清中ALT和AST水平及肝臟中SOD、MDA、iNOS、GSH和GSH-PX等含量;HE染色觀察肝臟組織病理損傷情況;Real-time PCR檢測肝組織中細胞因子的表達水平;Western blot檢測肝組織中 TLR4、p-JNK、及 p62、Keap-1、Bcl-2、Bax、Nrf-2 和 SOD-2的蛋白表達情況;分別采用Real-time PCR及Western blot檢測Nrf-2及其下游靶基因HO-1、GCLC和NQO-1的mRNA及蛋白水平變化。結果表明,沙棘多糖顯著降低APAP小鼠血清中ALT和AST水平。沙棘多糖提高了肝臟中SOD、GSH和GSH-PX的水平,降低了 MDA、NO和iNOS的水平。HE染色結果也表明沙棘多糖能有效緩解APAP誘導的肝毒性。沙棘多糖抑制了 TLR4、p-JNK的表達并上調了 Bcl-2/Bax。沙棘多糖抑制了 APAP小鼠中炎性細胞因子TNF-α和IL-6的表達并促進IL-10的表達;進一步研究結果表明,沙棘多糖下調Keap-1的表達、促進Nrf-2核轉位及其下游靶基因HO-1和SOD-2的活化。本研究表明,沙棘多糖能夠保護APAP誘導的肝損傷。該保護作用與其抗炎和抗氧化功能有關。沙棘多糖通過調控TLR4-p-JNK以及Nrf-2/HO-l-SOD-2信號通路發(fā)揮保肝作用。本研究為開發(fā)沙棘多糖類綠色藥物奠定基礎。
[Abstract]:Drug-induced liver injury (DILI) is a liver injury caused by the drug itself and its metabolites. It is the main cause of acute liver failure. The seabuckthorn fruit is considered to be of high medicinal value in Tibetan and Mongolian medicine, and can be used to treat a variety of diseases, but the polysaccharide extract of seabuckthorn fruit (Seabucthorn berry po1ysac) Charide, SP) little study on the treatment of DILI. This experiment was conducted to explore the protective effect and mechanism of seabuckthorn polysaccharides on drug induced liver injury induced by Acetaminophen (APAP) induced liver injury in mice and to provide a scientific basis for the development of new green liver protection drugs for the development of.C57BL/6 male mice randomly divided into six groups, that is, blank control Group (Ctrl), APAP model group (APAP), N- acetyl cysteine group (NAC), Hippophae rhamnoides polysaccharide low dose group (APAP/SP100), seabuckthorn polysaccharide high dose group (APAP/SP200), seabuckthorn polysaccharide control group (SP200), seabuckthorn polysaccharide low, high dose group and control group with 100200200mg.kg-1 SP 30 days after continuous perfusion of 100200200mg.kg-1 SP, intraperitoneal injection of paracetamol (350mg.kg-1) to construct DILI The model, NAC (150mg.kg-1) was killed in 1h after.16h injection, and the serum and liver samples were collected. The levels of serum ALT and AST and the content of SOD, MDA, iNOS, GSH and GSH-PX in the liver were detected, and the pathological damage of liver tissue was observed by HE staining. The protein expressions of TLR4, p-JNK, and p62, Keap-1, Bcl-2, Bax, Nrf-2 and SOD-2 were measured in the liver tissue, and Real-time PCR and Western blot and its downstream target genes were used respectively. The results showed that the Seabuckthorn polysaccharides decreased significantly in the serum of mice and the increase of seabuckthorn polysaccharide The level of SOD, GSH and GSH-PX in the liver decreased the level of MDA, NO and iNOS. The results also showed that the Seabuckthorn polysaccharide could effectively alleviate the liver toxicity induced by APAP. The Seabuckthorn polysaccharide inhibited the TLR4, the p-JNK expression and the inhibition of the expression of inflammatory cytokines and the expression of inflammatory cytokines in APAP mice. The further study shows that Seabuckthorn polysaccharides downregulate the expression of Keap-1, promote the Nrf-2 nuclear transposition and the activation of the downstream target gene HO-1 and SOD-2. This study shows that the Seabuckthorn polysaccharide can protect the liver injury induced by APAP. The protective effect is related to its anti-inflammatory and antioxidant functions. Seabuckthorn polysaccharides can be controlled by TLR4-p-JNK and Nrf-2/HO- L-SOD-2 signaling pathway plays a role in liver protection. This study lays the foundation for developing Seabuckthorn polysaccharide green drugs.

【學位授予單位】：內蒙古農業(yè)大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R285.5

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