益气养阴方对Graves病小鼠白细胞保护作用及其机制的研究
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摘要
目的
本课题立足于中医中药,开展益气养阴方对Graves病小鼠白细胞保护作用及其机理研究,用基因枪给小鼠造模,选取小鼠外周血白细胞计数、甲状腺功能、甲状腺组织学病理变化、细胞凋亡相关基因、IL-13、PPAR-Y等指标进行检测,深入探讨并初步揭示益气养阴方对GD白细胞保护作用及其作用机理,提供药效学理论依据,完善益气养阴方系统研究；进一步发挥中医药特色与优势,提高益气养阴方对GD及其并发症的临床疗效,减少西药抗甲状腺药物毒、副作用；同时,比较益气养阴方不同剂量之间的疗效差异,探讨益气养阴方的组方合理性,为进一步开发新药物奠定理论基础与实验依据。
方法
采用基因枪免疫Balb/c雌性小鼠建立GD模型,再将造模后GD小鼠随机分为五组：1模型组；2益气养阴方低剂量组；3益气养阴方中剂量组；4益气养阴方高剂量组；5他巴唑组；另一组是未造模的正常对照组。分别对各组应用益气养阴方高、中、低剂量和西药干预治疗,并运用放射免疫分析法检测甲状腺激素；对核转录因子PPAR-γ采用免疫组化法；逆转录多聚酶链法(RT-PCR)等方法检测细胞凋亡相关基因、IL-13的表达；运用流式细胞仪检测骨髓细胞周期及CD45分子的表达
结果
1小鼠外周血白细胞计数的实验结果
中药益气养阴方高、中、低剂量组和模型组、正常对照组比较没有显著性差异,P>0.05；与西药组比较有非常显著性差异,P<0.01；西药组与正常对照组比较,有非常显著性差异,P<0.01；模型组和正常对照组比较,没有显著性差异,P>0.05。2 GD小鼠甲状腺激素的实验结果
模型组小鼠的血清FT3、FT4明显升高,与正常对照组比较有非常显著性差异(P<0.01),尤以FT4升高更为明显,进一步说明我们的造模是成功的。
中药益气养阴方高剂量组和中药中剂量组比较有显著性差异,P<0.05,与中药低剂量组之间比较有非常显著性差异,P<0.01；表明在改善甲状腺功能方面,中药高剂量较中药中、低剂量效果好。中药高剂量组和他巴唑组与正常对照组比较没有显著性差异,P>0.05；中药中、低剂量组与他巴唑组相比,差异显著,P<0.01；中药高剂量组与他巴唑组比较没有显著性差异,P>0.05。
3小鼠骨髓细胞CD45分子表达的实验结果
CD45分子表达是通过横断的CD45+细胞道数来表现的。正常对照组CD45+细胞的通过率最高,为99.59%；中药高剂量组CD45+细胞的通过率为98.57%；中剂量组为98.39%；低剂量组为97.51%；这三者均与模型组、正常对照组比较有非常显著性差异,P<0.01；他巴唑组为94.22%,与中药高、中剂量组、正常对照组比较有非常显著性差异,P<0.01；模型组为91-26%,与中药高、中、低剂量组比较有非常显著性差异,P<0.01；与正常对照组、他巴唑组比较没有显著性差异,P>0.05。上述比较结果表明经益气养阴中药治疗,小鼠骨髓细胞CD45分子表达增加,这也意味着CD45+细胞的通过道数增加。
4小鼠骨髓细胞凋亡相关因子bax,bcl-2mRNA表达的实验结果
模型组baxmRNA表达水平有所降低,与正常对照组比较没有显著性差异,P>0.05；西药他巴唑组baxmRNA表达明显增高,与正常对照组比较有非常显著性差异,P<0.01；益气养阴方高、中剂量组与模型组、正常对照组比较没有显著性差异,P>0.05；益气养阴方低剂量组、他巴唑组与模型组、正常对照组比较有非常显著性差异,P<0.01。
模型组bcl-2mRNA表达水平有所升高,与正常对照组比较没有显著性差异,P>0.05；西药他巴唑组bcl-2mRNA表达明显降低,与正常对照组比较有非常显著性差异,P<0.01；益气养阴方高、中剂量组与模型组、正常对照组比较没有显著性差异,P>0.05；益气养阴方低剂量组、他巴唑组与模型组比较有显著性差异,P<0.05；益气养阴方低剂量组与正常对照组比较有显著性差异,P<0.05；他巴唑组与正常对照组比较,差异非常显著,P<0.01。
5小鼠IL-13mRNA的实验结果
模型组IL-13mRNA表达水平有所降低,与正常对照组比较没有显著性差异,P>0.05；西药他巴唑组IL-13mRNA表达明显降低,与正常对照组和模型组比较有显著性差异,P<0.01；中药治疗组的IL-13mRNA表达与正常对照组比较没有显著性差异,P>0.05。经中药益气养阴方治疗,小鼠IL-13mRNA的表达下调,即中药高剂量组表达最低,依次增高。表明中药益气养阴方有促进免疫细胞成熟、活化、增殖和免疫调节的作用。
6小鼠PPAR-γ的实验结果
PPAR-γ免疫反应阳性细胞为细胞核染成棕黄色或有棕黄色颗粒沉积.模型组小鼠PPARγ表达量较少(+).经中药益气养阴方治疗,小鼠PPAR-γ的表达上调。益气养阴高剂量组PPAR-γ表达显著增加(++++)；益气养阴中剂量组PPAR-γ表达(+++)；依次表达下调。
结论
1用基因枪免疫Balb/c雌性小鼠构建的GD动物模型,表达出动物GD主要特征,用其进行药物及病理等方面的研究具有可行性和实用性。
2中药益气养阴方能够改善甲状腺激素水平,具有治疗GD的作用。中药高剂量效果与他巴唑相当,中药中、低剂量效果则不及。
3中药益气养阴方既能治疗GD,同时又不至于引起外周血白细胞的减少,避免了西药的毒、副作用,效果优于他巴唑。中药高剂量效果优于中药中、低剂量。
4中药益气养阴方对GD白细胞的保护作用体现在它能调节Graves病小鼠的骨髓细胞凋亡水平,抑制骨髓细胞凋亡,使骨髓细胞凋亡恢复正常。其对骨髓细胞凋亡抑制,使白细胞升高,增加免疫力,这一点可能是益气养阴方对白细胞保护作用机制所在,而bcl-2、bax基因可能是其作用靶点。
Objective
The research is based on traditional chinese medicine to lunch a protection and mechanism research of Yiqiyangyin decoction to leucocyte of experimental GD mice.we used gene gun to establish mice model and then detected peripheral white blood cell count of mice,thyroid function(FTI),pathological change of thyroid histology,apoptosis-related genes,IL-13, PPAR-γand other indexes.we gave a in-depth exploration of protection and mechanism research of Yiqiyangyin decoction to leucocyte of experimental GD mice,made a preliminary revelation of it,provide pharmacological basis,and accomplish its research; we can improve curative effect of Yiqiyangyin decoction to GD and its complications,reduce the toxic side effects of western anti-thyroid drugs to further improve Chinese medicine characteristics and advantages;meanwhile,we compared the efficacy of different doses of the prescription, probe into its prescription-making rationality, lay the theoretical foundation and experimental basis for further drug discovery.
Methods
GD animal model established by female Balb/c mice immunized with gene gun were random into five groups:1 model group;2 C-H group;3 C-M group;4 C-L group;5 methimazole group;6 normal control group. All the group were given intervening therapy with high,middle,low dose of Yiqiyangyin decoction or western medicine, RIA was used to detect TH;immunohistochemistry to nuclear transcription factor PPAR-γ;RT-PCR to apoptosis-related genes expression of IL-13;FCM to marrow cell circle and expression of CD45 antigen.
Results
1 Experimental result of mice peripheral white blood cell count
C-H group, C-M group, C-L group, model group and normal control group had no significant difference, P>0.05;but compared with western medicine, the difference is significant,P<0.05;there had significant difference between western medicine group and normal group with P<0.01;there has significant difference between model group and normal group with P< 0.05.
2 Experiment result of GD mice TH
The mice serum FT3 and FT4 of model group increased obviously, with a significant difference compared with normalgroup (P<0.01),especially FT4,which was shown that our model-making were successful.
There had significant difference between C-M group and C-H group, P<0.05;There had very significant difference between C-H group with C-L group, P<0.01;which manifested that C-H group had a more effective result than C-M group and C-L group in improving thyroid function. C-H group, methimazole group and normal group had no significant difference,P>0.05;
3 Experiment result of mice marrow cell CD45 molecule expression.
CD45 molecule expression was showed by the track numbers CD45+ accrossed. The CD45+ cell of normalgroup has the highest through rate,with 99.59%:the through rate of CD45+cell of C-H group(98.57 %),C-M group (98.39%),C-L group(98.39%)had significant difference with model and normal group,P<0.01;methimazole group(94.22%)had significant difference with C-H group, C-M group and normal group,P<0.01.model group (91.26%) had significant difference with C-H group, C-M group,C-L group,P<0.01;but it had no significant difference with normal and methimazole group, P>0.05.They all showed that after the treatment of Yiqiyangyin chinese medicine,the CD45 molecule expression of mice marrow cell increased,which also mean the track number CD45+ cell passed increased.
4 Experiment result of the expression of mice marrow cell apoptosis-related gene-bax,bcl-2mRNA
BaxmRNA expression ability of model group had modest reduction,which has no significant difference with blank group, P>0.05;the tapazole group increased apparently, which has significant difference with normal group,P<0.01;there have no significant difference among C-H group, C-M group,model and normal group,P>0.05; there have significant difference among C-L group,tapazole,modeland normal group, P<0.01.
Bcl-2mRNA expression ability of model group had modest increase,which has no significant difference with normal group, P>0.05;the tapazole group decreased markedly,which has significant difference with normal group,P<0.01;there have no significant difference among C-H group,C-M group, model and normal group,P>0.05;C-L group, tapazole group have significant difference with model group, P<0.05;C-L group has significant difference with normal group, P<0.05;tapazole group has significant difference with normal group,P<0.01.
5 Experiment result of mice IL-13mRNA
IL-13mRNA expression ability of model group had modest decrease, which has no significant difference with normal group,P>0.05;the tapazole group decreased markedly,which has significant difference with normal group,P<0.01:there has no significant difference in the IL-13mRNA expression between chinese medicine treatment group and normal group,P>0.05. After the treatment of Yiqiyangyin chinese medicine,the expression of mice IL-13mRNA has made a down-regulation, which mean C-H group express the lowest,with gradually increased.these all show that the Yiqiyangyin chinese medicine made a promoter action in the ripe,activization,mutiplication of immune cell and immune regulation.
6 Experiment result of mice PPAR-γ
The PPAR-γimmunoreactivity cells were sediment whose nucleolus dyed claybank or had claybank particle.mice PPAR-γexpression level of model group was less,and after the treatment of Yiqiyangyin chinese medicine,its expression level turn to up-regulation. the mice PPAR-γexpression of C-H group increased markedly(++++),and C-M group (+++);gradually down-regulation.
Conclusion
1.GD animal model established by female Balb/c mice immunized with gene gun expressed GD animals main characteristic,and were feasible and applied in pharmic and pathological research
2.Chinese medicine Yiqiyangyin decoction can improve TH level and cure GD patients.C-H and C-M are equivalent in treating GD patients with tapazole,however,C-L is much less.
3. Not only can Chinese medicine Yiqiyangyin decoction treat GD patients,but also not lead to the reduction of eripheral white blood cell count, which avoid the virulent and side effect of western medicine. Its effects is superior than tapazole.C-H and C-M is better than C-L.
4.The protection of TCM Yiqiyangyin decoction to GD white cell reflect in it can regulate Graves mices marrow cell apoptosis level,restrain marrow cell apoptosis and make it get to right level.The point of restraining marrow cell apoptosis,rising white cell,and improving immune system may be the mechanism of action for Yiqiyangyin decoction to protect white cell,and Bcl-2,bax gen may be its target.
本课题立足于中医中药,开展益气养阴方对Graves病小鼠白细胞保护作用及其机理研究,用基因枪给小鼠造模,选取小鼠外周血白细胞计数、甲状腺功能、甲状腺组织学病理变化、细胞凋亡相关基因、IL-13、PPAR-Y等指标进行检测,深入探讨并初步揭示益气养阴方对GD白细胞保护作用及其作用机理,提供药效学理论依据,完善益气养阴方系统研究；进一步发挥中医药特色与优势,提高益气养阴方对GD及其并发症的临床疗效,减少西药抗甲状腺药物毒、副作用；同时,比较益气养阴方不同剂量之间的疗效差异,探讨益气养阴方的组方合理性,为进一步开发新药物奠定理论基础与实验依据。
方法
采用基因枪免疫Balb/c雌性小鼠建立GD模型,再将造模后GD小鼠随机分为五组：1模型组；2益气养阴方低剂量组；3益气养阴方中剂量组；4益气养阴方高剂量组；5他巴唑组；另一组是未造模的正常对照组。分别对各组应用益气养阴方高、中、低剂量和西药干预治疗,并运用放射免疫分析法检测甲状腺激素；对核转录因子PPAR-γ采用免疫组化法；逆转录多聚酶链法(RT-PCR)等方法检测细胞凋亡相关基因、IL-13的表达；运用流式细胞仪检测骨髓细胞周期及CD45分子的表达
结果
1小鼠外周血白细胞计数的实验结果
中药益气养阴方高、中、低剂量组和模型组、正常对照组比较没有显著性差异,P>0.05；与西药组比较有非常显著性差异,P<0.01；西药组与正常对照组比较,有非常显著性差异,P<0.01；模型组和正常对照组比较,没有显著性差异,P>0.05。2 GD小鼠甲状腺激素的实验结果
模型组小鼠的血清FT3、FT4明显升高,与正常对照组比较有非常显著性差异(P<0.01),尤以FT4升高更为明显,进一步说明我们的造模是成功的。
中药益气养阴方高剂量组和中药中剂量组比较有显著性差异,P<0.05,与中药低剂量组之间比较有非常显著性差异,P<0.01；表明在改善甲状腺功能方面,中药高剂量较中药中、低剂量效果好。中药高剂量组和他巴唑组与正常对照组比较没有显著性差异,P>0.05；中药中、低剂量组与他巴唑组相比,差异显著,P<0.01；中药高剂量组与他巴唑组比较没有显著性差异,P>0.05。
3小鼠骨髓细胞CD45分子表达的实验结果
CD45分子表达是通过横断的CD45+细胞道数来表现的。正常对照组CD45+细胞的通过率最高,为99.59%；中药高剂量组CD45+细胞的通过率为98.57%；中剂量组为98.39%；低剂量组为97.51%；这三者均与模型组、正常对照组比较有非常显著性差异,P<0.01；他巴唑组为94.22%,与中药高、中剂量组、正常对照组比较有非常显著性差异,P<0.01；模型组为91-26%,与中药高、中、低剂量组比较有非常显著性差异,P<0.01；与正常对照组、他巴唑组比较没有显著性差异,P>0.05。上述比较结果表明经益气养阴中药治疗,小鼠骨髓细胞CD45分子表达增加,这也意味着CD45+细胞的通过道数增加。
4小鼠骨髓细胞凋亡相关因子bax,bcl-2mRNA表达的实验结果
模型组baxmRNA表达水平有所降低,与正常对照组比较没有显著性差异,P>0.05；西药他巴唑组baxmRNA表达明显增高,与正常对照组比较有非常显著性差异,P<0.01；益气养阴方高、中剂量组与模型组、正常对照组比较没有显著性差异,P>0.05；益气养阴方低剂量组、他巴唑组与模型组、正常对照组比较有非常显著性差异,P<0.01。
模型组bcl-2mRNA表达水平有所升高,与正常对照组比较没有显著性差异,P>0.05；西药他巴唑组bcl-2mRNA表达明显降低,与正常对照组比较有非常显著性差异,P<0.01；益气养阴方高、中剂量组与模型组、正常对照组比较没有显著性差异,P>0.05；益气养阴方低剂量组、他巴唑组与模型组比较有显著性差异,P<0.05；益气养阴方低剂量组与正常对照组比较有显著性差异,P<0.05；他巴唑组与正常对照组比较,差异非常显著,P<0.01。
5小鼠IL-13mRNA的实验结果
模型组IL-13mRNA表达水平有所降低,与正常对照组比较没有显著性差异,P>0.05；西药他巴唑组IL-13mRNA表达明显降低,与正常对照组和模型组比较有显著性差异,P<0.01；中药治疗组的IL-13mRNA表达与正常对照组比较没有显著性差异,P>0.05。经中药益气养阴方治疗,小鼠IL-13mRNA的表达下调,即中药高剂量组表达最低,依次增高。表明中药益气养阴方有促进免疫细胞成熟、活化、增殖和免疫调节的作用。
6小鼠PPAR-γ的实验结果
PPAR-γ免疫反应阳性细胞为细胞核染成棕黄色或有棕黄色颗粒沉积.模型组小鼠PPARγ表达量较少(+).经中药益气养阴方治疗,小鼠PPAR-γ的表达上调。益气养阴高剂量组PPAR-γ表达显著增加(++++)；益气养阴中剂量组PPAR-γ表达(+++)；依次表达下调。
结论
1用基因枪免疫Balb/c雌性小鼠构建的GD动物模型,表达出动物GD主要特征,用其进行药物及病理等方面的研究具有可行性和实用性。
2中药益气养阴方能够改善甲状腺激素水平,具有治疗GD的作用。中药高剂量效果与他巴唑相当,中药中、低剂量效果则不及。
3中药益气养阴方既能治疗GD,同时又不至于引起外周血白细胞的减少,避免了西药的毒、副作用,效果优于他巴唑。中药高剂量效果优于中药中、低剂量。
4中药益气养阴方对GD白细胞的保护作用体现在它能调节Graves病小鼠的骨髓细胞凋亡水平,抑制骨髓细胞凋亡,使骨髓细胞凋亡恢复正常。其对骨髓细胞凋亡抑制,使白细胞升高,增加免疫力,这一点可能是益气养阴方对白细胞保护作用机制所在,而bcl-2、bax基因可能是其作用靶点。
Objective
The research is based on traditional chinese medicine to lunch a protection and mechanism research of Yiqiyangyin decoction to leucocyte of experimental GD mice.we used gene gun to establish mice model and then detected peripheral white blood cell count of mice,thyroid function(FTI),pathological change of thyroid histology,apoptosis-related genes,IL-13, PPAR-γand other indexes.we gave a in-depth exploration of protection and mechanism research of Yiqiyangyin decoction to leucocyte of experimental GD mice,made a preliminary revelation of it,provide pharmacological basis,and accomplish its research; we can improve curative effect of Yiqiyangyin decoction to GD and its complications,reduce the toxic side effects of western anti-thyroid drugs to further improve Chinese medicine characteristics and advantages;meanwhile,we compared the efficacy of different doses of the prescription, probe into its prescription-making rationality, lay the theoretical foundation and experimental basis for further drug discovery.
Methods
GD animal model established by female Balb/c mice immunized with gene gun were random into five groups:1 model group;2 C-H group;3 C-M group;4 C-L group;5 methimazole group;6 normal control group. All the group were given intervening therapy with high,middle,low dose of Yiqiyangyin decoction or western medicine, RIA was used to detect TH;immunohistochemistry to nuclear transcription factor PPAR-γ;RT-PCR to apoptosis-related genes expression of IL-13;FCM to marrow cell circle and expression of CD45 antigen.
Results
1 Experimental result of mice peripheral white blood cell count
C-H group, C-M group, C-L group, model group and normal control group had no significant difference, P>0.05;but compared with western medicine, the difference is significant,P<0.05;there had significant difference between western medicine group and normal group with P<0.01;there has significant difference between model group and normal group with P< 0.05.
2 Experiment result of GD mice TH
The mice serum FT3 and FT4 of model group increased obviously, with a significant difference compared with normalgroup (P<0.01),especially FT4,which was shown that our model-making were successful.
There had significant difference between C-M group and C-H group, P<0.05;There had very significant difference between C-H group with C-L group, P<0.01;which manifested that C-H group had a more effective result than C-M group and C-L group in improving thyroid function. C-H group, methimazole group and normal group had no significant difference,P>0.05;
3 Experiment result of mice marrow cell CD45 molecule expression.
CD45 molecule expression was showed by the track numbers CD45+ accrossed. The CD45+ cell of normalgroup has the highest through rate,with 99.59%:the through rate of CD45+cell of C-H group(98.57 %),C-M group (98.39%),C-L group(98.39%)had significant difference with model and normal group,P<0.01;methimazole group(94.22%)had significant difference with C-H group, C-M group and normal group,P<0.01.model group (91.26%) had significant difference with C-H group, C-M group,C-L group,P<0.01;but it had no significant difference with normal and methimazole group, P>0.05.They all showed that after the treatment of Yiqiyangyin chinese medicine,the CD45 molecule expression of mice marrow cell increased,which also mean the track number CD45+ cell passed increased.
4 Experiment result of the expression of mice marrow cell apoptosis-related gene-bax,bcl-2mRNA
BaxmRNA expression ability of model group had modest reduction,which has no significant difference with blank group, P>0.05;the tapazole group increased apparently, which has significant difference with normal group,P<0.01;there have no significant difference among C-H group, C-M group,model and normal group,P>0.05; there have significant difference among C-L group,tapazole,modeland normal group, P<0.01.
Bcl-2mRNA expression ability of model group had modest increase,which has no significant difference with normal group, P>0.05;the tapazole group decreased markedly,which has significant difference with normal group,P<0.01;there have no significant difference among C-H group,C-M group, model and normal group,P>0.05;C-L group, tapazole group have significant difference with model group, P<0.05;C-L group has significant difference with normal group, P<0.05;tapazole group has significant difference with normal group,P<0.01.
5 Experiment result of mice IL-13mRNA
IL-13mRNA expression ability of model group had modest decrease, which has no significant difference with normal group,P>0.05;the tapazole group decreased markedly,which has significant difference with normal group,P<0.01:there has no significant difference in the IL-13mRNA expression between chinese medicine treatment group and normal group,P>0.05. After the treatment of Yiqiyangyin chinese medicine,the expression of mice IL-13mRNA has made a down-regulation, which mean C-H group express the lowest,with gradually increased.these all show that the Yiqiyangyin chinese medicine made a promoter action in the ripe,activization,mutiplication of immune cell and immune regulation.
6 Experiment result of mice PPAR-γ
The PPAR-γimmunoreactivity cells were sediment whose nucleolus dyed claybank or had claybank particle.mice PPAR-γexpression level of model group was less,and after the treatment of Yiqiyangyin chinese medicine,its expression level turn to up-regulation. the mice PPAR-γexpression of C-H group increased markedly(++++),and C-M group (+++);gradually down-regulation.
Conclusion
1.GD animal model established by female Balb/c mice immunized with gene gun expressed GD animals main characteristic,and were feasible and applied in pharmic and pathological research
2.Chinese medicine Yiqiyangyin decoction can improve TH level and cure GD patients.C-H and C-M are equivalent in treating GD patients with tapazole,however,C-L is much less.
3. Not only can Chinese medicine Yiqiyangyin decoction treat GD patients,but also not lead to the reduction of eripheral white blood cell count, which avoid the virulent and side effect of western medicine. Its effects is superior than tapazole.C-H and C-M is better than C-L.
4.The protection of TCM Yiqiyangyin decoction to GD white cell reflect in it can regulate Graves mices marrow cell apoptosis level,restrain marrow cell apoptosis and make it get to right level.The point of restraining marrow cell apoptosis,rising white cell,and improving immune system may be the mechanism of action for Yiqiyangyin decoction to protect white cell,and Bcl-2,bax gen may be its target.
引文
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