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广藿香油抗病毒的物质基础研究
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摘要
目的:通过广藿香油体外抗流感病毒、呼吸道合胞病毒、腺病毒、柯萨奇病毒及单纯疱疹病毒的效果,筛选出敏感病毒株,研究广藿香油体外抗病毒的作用方式,并通过体内验证广藿香油抗病毒效果。从广藿香油主要物质成分广藿香醇和广藿香酮对以上5种病毒的效果,初步探讨广藿香油抗病毒的药效物质基础及作用原理。
     方法:建立流感病毒(HINI)感染MDCK细胞、呼吸道合胞病毒(RSV)和腺病毒(ADV)感染Hep-2细胞、柯萨奇病毒(CVB3)感染Hela细胞模型和单纯疱疹病毒(HSV-I)感染Vero细胞模型,以细胞病变效应(CPE)、噻唑蓝(MTT)法作为观察和检测指标,观察不同浓度广藿香油对细胞的毒性及体外抗病毒效果,筛选敏感病毒株,根据病毒复制周期特点研究药物作用方式,并用最敏感病毒株腹腔注射小鼠建立体内致病模型,观察广藿香油经腹腔注射给药对模型小鼠的一般情况、生存率、心肝肺肾脏器指数,病理切片和血清生化指标的影响,验证广藿香油体内抗病毒效果。另外从广藿香油主要物质成分广藿香醇和广藿香酮对细胞的毒性及体外抗病毒效果,筛选出敏感病毒株,研究药物与病毒的作用方式,采用常规PCR和Real-time PCR的方法定位药物对病毒的作用靶点,初步探讨广藿香油抗病毒的药效物质基础及作用原理。
     结果:广藿香油及其主要单体成分广藿香醇和广藿香酮对MDCK、Hep-2、Vero和Hela细胞的毒性结果都基本一致,广藿香油、广藿香醇和广藿香酮对4种细胞的TC50浓度分别为0.101mg/ml、0.125mg/ml和0.071mg/ml,TCo浓度分别为0.092mg/ml、0.031mg/ml和0.063mg/ml;广藿香油、广藿香醇和广藿香酮能不同程度的抑制H1N1、CVB3和ADV所致的细胞病变,对RSV的抑制作用低或无作用,对HSV-1几乎无抑制作用。广藿香油、广藿香醇和广藿香酮对H1N1的IC50分别为0.088mg/ml、0.031mg/ml和0.063mg/mI,治疗指数(TI)为1.13、4.0和1.13;对的IC50分别为0.08mg/ml、0.063mg/ml和0.067mg/ml,TI为1.25、2.0和1.06;对ADV的IC50分别为0.084mg/ml、0.063mg/ml和0.063mg/ml,TI为1.20、4.0和1.13。广藿香油和广藿香醇对病毒的作用优于广藿香酮。广藿香油和广藿香醇对病毒的直接作用效果都优于抗病毒吸附和抗病毒生物合成,而且在直接作用方面,同一浓度下广藿香油对CVB3的抑制率高于H1N1和ADV,广藿香醇对ADV的抑制率高于H1N1和CVB3。PCR和Real-time PCR结果显示广藿香醇对ADV病毒的Hexon基因有一定的破坏作用。广藿香油腹腔注射给药LD50为4.441mg/g,95%预测区间为(3.768,5.317mg/g)。广藿香油对CVB3腹腔注射Balb/c小鼠建立的病毒性心肌炎动物模型有一定治疗作用,其中0.096g/kg浓度组的小鼠存活率、心脏病变缓解程度都高于阳性药物组,而且对肝肾等脏器有一定保护作用,能增加SOD活性,明显降低MDA和TNF-α水平,会略微降低LDH和CK-MB水平。
     结论:在体外抗病毒实验中,广藿香油显示出抗柯萨奇病毒、腺病毒和甲型流感病毒的作用,对呼吸道合胞病毒和单纯疱疹病毒几乎无作用,其中对柯萨奇病毒的抑制作用最明显,同时对柯萨奇病毒引起的体内致病模型也有治疗效果,说明广藿香油体内外具有抗病毒效果。广藿香油的主要单体成分广藿香醇和广藿香酮也有抗病毒作用,其中广藿香醇的抗病毒效果明显优于广藿香酮,在抗腺病毒方面作用最明显,作用靶点以腺病毒负责翻译衣壳蛋白的Hexon基因为主。
Obejctive:Observing the effect of patchouli oil against influenza virus, respiratory syncytial virus, adenovirus, Coxsackie virus and herpes simplex virus in vitro. Screening the sensitive viruses to research the antivirus action of the drug. Verify the antiviral effect of Patchouli oil on viral animal model in vivo. Investigate the antivirus effect of the tow main components of patchouli oil which are patchouli alcohol and patchoulenone to discussing the antiviral pharmacodynamic substance foundation and action principle of patchouli oi.
     Methods:Establish models of influenza virus (H1N1) infecting MDCK cell, respiratory syncytial virus (RSV) and adenovirus (ADV) infecting Hep-2cell, Coxsackie virus (CVB3) infecting Hela cell and herpes simplex virus (HSV-1) infecting Vero cell respectively. Use CPE and MTT as the observation and detection methods, to investigate the drug toxicity to the cells and the antiviral effect of different concentrations of patchouli oil, screeing the sensitive viruses to the drug. Researching the drug action based on the virus replication characteristic. Establish the viral infected mice model with the most sensitive virus according to intraperitoneal injection, observing the influences of the model general condition, survival rate, heart,liver,lung and kidney index, pathological sections and serum biochemical index by patchouli oil with intraperitoneal injection. Verifying the antiviral effect of patchouli oil in vivo. On the other hand, investigate the drug toxicity to the cells and the antiviral effect of different concentrations of patchouli alcohol and patchoulenone which are the main mate composition of patchouli oil, screeing the sensitive viruses, researching the drug action to virus. Using normal PCR and Real-time PCR to locate the target of drug action to virus. Explore the antiviral pharmacodynamic substance foundation of anti-virus and principle of patchouli oil.
     Results:The cytotoxicity of Patchouli oil, patchouli alcohol and patchoulenone to MDCK, Hep-2, Vero and Hela cells are basically identical. The TC50of Patchouli oil, patchouli alcohol and patchoulenone to the cells are0.101mg/ml,0.125mg/ml and0.071mg/ml, the TC0are0.092mg/ml,0.031mg/ml and0.063mg/ml. Patchouli oil, patchouli alcohol and patchoulenone could inhibit the H1N1, CVB3and ADV virus induced cell lesion in different degrees, there's no inhibition or very low on RSV and no inhibition on HSV-1. The IC50of Patchouli oil, patchouli alcohol and patchoulenone to H1N1are0.088mg/ml,0.031mg/ml and0.063mg/ml,the therapeutic index (TI) is1.13,4.0and1.13; to CVB3are0.08mg/ml,0.063mg/ml and0.067mg/ml, TI are1.25,2.0and1.06; to ADV are0.084mg/ml,0.063mg/ml and0.063mg/ml,TI are1.20,4.0and1.13. Patchouli oil and patchouli alcohol are better than patchoulenone on the role of antivirus.Patchouli oil and patchouli alcohol on the direct action of the virus is superior to the anti-virus adsorption and antiviral biosynthesis. And in direct action, Patchouli oil on CVB3inhibition rate is higher than H1N1and ADV inhibition and patchouli alcohol on ADV inhibition rate is significantly higher than H1N1and CVB3inhibition under the same concentration. The result of PCR and Real-time PCR show that patchouli alcohol could damage the Hexon gene of ADV. The LD50of patchouli oil on mouse by intraperitoneal injection is4.441mg/g, the95%prediction interval is3.768,5.317mg/g. Patchouli oil has a certain therapeutic effect on viral myocarditis mice, the concentration group of0.096g/kg is higher than the positive drup group in the field of survival rate and cardiac remission, and has a certain protective effect on liver and kidney, can increase the SOD activity, decrease the MDA and TNF-α levels,slightly lower LDH and CK-MB level.
     Conclusion:In vitro antiviral experiment, patchouli oil show the ability of anti-Coxsackie virus, anti-adenovirus, anti-influenza A virus except anti-respiratory syncytial virus, the anti-Coxsackie virus effect is superior than others, meanwhile patchouli oil has a good antagonistic effect on Viral myocarditis mice model injected by CVB3in vivo, this means patchouli oil has antiviral effect in vivo and in vitro. Patchouli alcohol and patchoulenone which are the main monomer components of patchouli oil show antiviral effect, patchouli alcohol is better than patchoulenone. Patchouli alcohol is obviously in anti-adenovirus on the target of Hexon gene which is responsible for translation capsid protein of adenovirus.
引文
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