青黄散治疗骨髓增生异常综合征去甲基化作用效应机制研究
摘要
第一部分青黄散对DNMT1、DNMT3a、DNMT3b mRNA影响研究
目的：研究青黄散对骨髓增生异常综合征(MDS)患者甲基转移酶1(DNMT1)、甲基转移酶3a(DNMT3a)、甲基转移酶3b(DNMT3b) mRNA表达的影响。探讨外周血象改变与DNMT1、DNMT3a、DNMT3b变化之间的相关性,分析青黄散发挥疗效的作用机制。
方法：应用实时定量PCR技术检测30例MDS患者应用青黄散治疗前后骨髓细胞DNMT1、DNMT3a、DNMT3b mRNA相对定量,分析DNMT1、DMT3a、DNMT3b mRNA的变化情况；从疗效角度分析有效组及无效组DNMTs的变化情况；探讨DNMTs mRNA水平与治疗前后外周血象改变之间的相关性；应用多元回归方法建立血象变化数值与DNMTs的回归方程,通过DNMTs mRNA含量预测血象的变化。
结果：1.根据疗效判定标准对30例患者进行疗效评价,有效患者23人,无效患者7人,有效率为76.67%。2.对30例患者进行疗效评价,其中有效患者23例,治疗后Hgb、PLT明显升高(p<0.05)；无效患者7例,治疗后WBC、Hgb、PLT、ANC与治疗前相比无明显变化(P>0.05)。3.23例有效患者治疗后DNMT1与治疗前相比明显下降(p<0.05),7例无效患者治疗后DNMTs未见明显改变(P>0.05)。4.有效组患者治疗前DNMT1、DNMT3a、DNMT3b mRNA相对含量较无效组低,经治疗后有效组患者DNMT1mRNA相对含量仍较无效组低(P<0.05)。5.WBC (?)台疗后变化数值与治疗前DNMT3a mRNA相对定量的对数呈负相关,两者相关系数R是-0.41；HgB治疗后变化数值与治疗前DNMT1、DNMT3a mRNA相对定量的对数呈负相关,相关系数R分别为是-0.57及-0.67；PLT治疗后变化数值与治疗前DNMT1、DNMT3a、DNMT3b mRNA相对定量的对数呈负相关,相关系数R分别是-0.47、-0.37及-0.62,与治疗后DNMT3a mRNA相对定量的对数呈负相关,相关系数R是-0.41。6.经过多元回归分析,筛选出治疗前Dnmt1敞为预测外周血象变化的指标,分别得出Hgb、PLT变化与治疗前Dnmt1的相对定量对数的预测回归方程。
结论：青黄散能够抑制DNMT1mRNA的表达,通过降低甲基转移酶活性减少由SAM向DNA的甲基化过程,减轻了DNA甲基化,从而改善患者外周血象起到治疗作用。
第二部分青黄散对S-腺苷甲硫氨酸循环代谢影响研究
目的：研究青黄散对骨髓增生异常综合征(MDS)患者S-腺苷甲硫氨酸(SAM)代谢的影响。探讨外周血象改变与SAM及其代谢产物变化之间的相关性,探索青黄散去甲基化的作用机理。
方法：应用Elisa方法检测54例MDS患者青黄散治疗前后外周血清SAM、S-腺苷同型半胱氨酸(SAH)、同型半胱氨酸(HCY)的含量,分析SAM、SAH、HCY的变化情况；同时应用血细胞分析仪检测这54例患者治疗前后的外周血象,对入组患者进行疗效评价,从疗效角度及不同染色体核型对患者进行分组,分析不同组间SAM、SAH、HCY的变化情况；探讨SAM、SAH、HCY的变化水平与治疗前后外周血象改变之间的相关性。
结果：1.根据疗效判定标准对54例患者进行疗效评价,有效患者35人,无效患者19人,有效率为64.81%。2.54例患者中有效患者35例,治疗后Hgb、PLT明显升高(p<0.05)；无效患者19例,治疗后WBC、Hgb、PLT、ANC与治疗前相比无明显变化(P>0.05)。3.35例有效患者治疗后SAM含量并未见明显变化(P>0.05),SAH较治疗前下降(P<0.05),HCY较治疗前上升(P<0.05),SAM/SAH的比值较前上升(P<0.05),19例无效患者治疗后SAM、SAH、HCY、SAM/SAH未见明显改变(P>0.05)。4.将54例患者按不同染色体核型分为三组,比较组间SAM、SAH、HCY差异,经统计学检验,不同染色体核型组治疗前后SAM、SAH、HCY之间并无差异(P>0.05)。5.HgB治疗后变化数值与患者治疗前后HCY含量变化值呈正相关,两者相关系数R是0.33(P<0.05)；PLT治疗后变化数值与患者治疗前后HCY含量变化值呈正相关,两者相关系数R是0.35(P<0.01)。
结论：青黄散对SAM-SAH-HCY循环圈存在影响,由于青黄散对DNMT(?)表达量的影响导致了SAM向SAH的进一步代谢减弱,结果使SAM向DNA提供的甲基基团减少,降低了DNA的甲基化,从而改变MDS患者高甲基化状态起到治疗作用。
Part One To study effect of Qinghuang power treatment on DNMT1,DNMT3a,DNMT3b mRNA in MDS patients
Objective To study the effect of Qinghuang power on MDS patients'DNMT1, DNMT3a, DNMT3b mRNA expression and observe the correlations between Changes in peripheral blood cells and DNMT1, DNMT3a、DNMT3b. The Research Article focus on analysing Qinghuang power mechanism of therapeutic action.
Methods We analyses the changes of DNMT1, DNMT3a and DNMT3b mRNA relative quantitation which measured by a real-time quantitative PCR from30patients before and after treatment with Qinghuang powder. Peripheral blood cells were detected during the same period by hematology analyzer. After the test,the patients were divided into effective and ineffective groups according to clinical curative effects evaluation. The changes of DNMTs were observed respectively in the two groups. To discuss the correlations between DNMTs mRNA levels and changes in peripheral blood before and after the treatment. Maths model is built up to show the relationship of DNMTs mRNA levels and changes in peripheral blood using multiple linear regression analysis of experimental results,which can predict the change of blood cells by DNMTs mRNA content.
Results1.30cases of patients were evaluated by clinical curative effects evaluation,23patients were effective,7patients were ineffective, effective rate was76.67%;2Both Hgb and PLT were significantly increased effective group(p<0.05), nevertheless,the ineffective group was not(p>0.05).3.the level of DNMT1mRNA were decreased significantly in23effective cases compared with those before treatment (p<0.05), no significant changes were found in7ineffective cases (p>0.05)4. DNMT1DNMT3a DNMT3b mRNA relative content in valid group were lower than those in invalid group before treatment (P<0.05),The result was similar after treatment (P<0.05).5. The WBC change values demonstrated a negative correlation with DNMT3a mRNA relative quantitative logarithmic before treatment. their correlation coefficient is-0.41, The Hgb change values demonstrated a negative correlation both with DNMT1and with DNMT3a mRNA relative quantitative logarithmic before treatment. The correlation coefficient is-0.57and-0.67.The PLT change values demonstrated a negative correlation with DNMT1,DNMT3a and DNMT3b mRNA relative quantitative logarithmic before treatment.and also with DNMT3a mRNA. Correlation coefficient were-0.47,-0.37,-0.62and-0.41respectively.6.The three DNMTs mRNA factors affecting blood cells were analysed by multiple regression method and optimum equations were suggested for the main factor-Dnmtl mRNA relative quantitative logarithmic before treatment affecting Hgb and PLT.
Conclusion Qinghuang power mainly reflected on inhibition of DNMT1mRNA expression, It exert the therapeutic action on improving blood cells level by way of reducing methyltransferase activity and reducing methylation process from SAM to DNA.
Part Two To study effect of Qinghuang power treatment on S-adenosylmethionine meta-bolic circulation in MDS patients
Objective To study the effect of Qinghuang power on MDS patients' S-adenosylmethionine metabolic circulation and observe the correlations between changes in peripheral blood cells and SAM with its metabolic products. The Research Article focus on analysing Qinghuang power methylation pathway.
Methods We determined the serum contents of SAM,SAH,HCY measuring by Elisa from54patients before and after treatment with Qinghuang powder. Peripheral blood cells were detected during the same period by hematology analyzer. After the test,the patients were divided into effective and ineffective groups according to clinical curative effects evaluation and chromosomal karyotypes.The changes of SAM,SAH,HCY contents were observed respectively in the two groups. To discuss the correlations between changes of SAM,SAH,HCY contents and changes in peripheral blood before and after the treatment.
Results1.54cases of patients were evaluated by clinical curative effects evaluation,35patients were effective,19patients were ineffective, effective rate was64.81%;2Both Hgb and PLT were significantly increased in effective group (p<0.05), nevertheless,the ineffective group was not (p>0.05).3. No significant SAM content changes were observed in effective group (p>0.05).the level of SAH was decreased significantly after treatment (p <0.05). SAM:SAH ratio was increased after treatment (P<0.05);moreover,HCY contents rose in effective group (P<0.05), nevertheless, above data remained unchanged in19ineffective patients(P<0.05).4.54patients were split into three groups according to different chromosomal karyotypes.We compare the contents of SAM,SAH,HCY differences among three groups,and After statistics processing, the experiment result shows no evident differences among them (P>0.05).5. The Hgb change values demonstrated a positive correlation with HCY content before and after treatment. their correlation coefficient is0.33(P<0.05), The PLT change values demonstrated a positive correlation with HCY content before and after treatment.Their correlation coefficient is0.35(P<0.05)
Conclusion Qinghuang power influences SAM-SAH-HCY metabolic circulation.The inhibition of DNMT1mRNA induced by Qinghuang power causes metabolism weakness from SAM to SAH,which results reducing Methyl group transferred from SAM to DNA.
目的：研究青黄散对骨髓增生异常综合征(MDS)患者甲基转移酶1(DNMT1)、甲基转移酶3a(DNMT3a)、甲基转移酶3b(DNMT3b) mRNA表达的影响。探讨外周血象改变与DNMT1、DNMT3a、DNMT3b变化之间的相关性,分析青黄散发挥疗效的作用机制。
方法：应用实时定量PCR技术检测30例MDS患者应用青黄散治疗前后骨髓细胞DNMT1、DNMT3a、DNMT3b mRNA相对定量,分析DNMT1、DMT3a、DNMT3b mRNA的变化情况；从疗效角度分析有效组及无效组DNMTs的变化情况；探讨DNMTs mRNA水平与治疗前后外周血象改变之间的相关性；应用多元回归方法建立血象变化数值与DNMTs的回归方程,通过DNMTs mRNA含量预测血象的变化。
结果：1.根据疗效判定标准对30例患者进行疗效评价,有效患者23人,无效患者7人,有效率为76.67%。2.对30例患者进行疗效评价,其中有效患者23例,治疗后Hgb、PLT明显升高(p<0.05)；无效患者7例,治疗后WBC、Hgb、PLT、ANC与治疗前相比无明显变化(P>0.05)。3.23例有效患者治疗后DNMT1与治疗前相比明显下降(p<0.05),7例无效患者治疗后DNMTs未见明显改变(P>0.05)。4.有效组患者治疗前DNMT1、DNMT3a、DNMT3b mRNA相对含量较无效组低,经治疗后有效组患者DNMT1mRNA相对含量仍较无效组低(P<0.05)。5.WBC (?)台疗后变化数值与治疗前DNMT3a mRNA相对定量的对数呈负相关,两者相关系数R是-0.41；HgB治疗后变化数值与治疗前DNMT1、DNMT3a mRNA相对定量的对数呈负相关,相关系数R分别为是-0.57及-0.67；PLT治疗后变化数值与治疗前DNMT1、DNMT3a、DNMT3b mRNA相对定量的对数呈负相关,相关系数R分别是-0.47、-0.37及-0.62,与治疗后DNMT3a mRNA相对定量的对数呈负相关,相关系数R是-0.41。6.经过多元回归分析,筛选出治疗前Dnmt1敞为预测外周血象变化的指标,分别得出Hgb、PLT变化与治疗前Dnmt1的相对定量对数的预测回归方程。
结论：青黄散能够抑制DNMT1mRNA的表达,通过降低甲基转移酶活性减少由SAM向DNA的甲基化过程,减轻了DNA甲基化,从而改善患者外周血象起到治疗作用。
第二部分青黄散对S-腺苷甲硫氨酸循环代谢影响研究
目的：研究青黄散对骨髓增生异常综合征(MDS)患者S-腺苷甲硫氨酸(SAM)代谢的影响。探讨外周血象改变与SAM及其代谢产物变化之间的相关性,探索青黄散去甲基化的作用机理。
方法：应用Elisa方法检测54例MDS患者青黄散治疗前后外周血清SAM、S-腺苷同型半胱氨酸(SAH)、同型半胱氨酸(HCY)的含量,分析SAM、SAH、HCY的变化情况；同时应用血细胞分析仪检测这54例患者治疗前后的外周血象,对入组患者进行疗效评价,从疗效角度及不同染色体核型对患者进行分组,分析不同组间SAM、SAH、HCY的变化情况；探讨SAM、SAH、HCY的变化水平与治疗前后外周血象改变之间的相关性。
结果：1.根据疗效判定标准对54例患者进行疗效评价,有效患者35人,无效患者19人,有效率为64.81%。2.54例患者中有效患者35例,治疗后Hgb、PLT明显升高(p<0.05)；无效患者19例,治疗后WBC、Hgb、PLT、ANC与治疗前相比无明显变化(P>0.05)。3.35例有效患者治疗后SAM含量并未见明显变化(P>0.05),SAH较治疗前下降(P<0.05),HCY较治疗前上升(P<0.05),SAM/SAH的比值较前上升(P<0.05),19例无效患者治疗后SAM、SAH、HCY、SAM/SAH未见明显改变(P>0.05)。4.将54例患者按不同染色体核型分为三组,比较组间SAM、SAH、HCY差异,经统计学检验,不同染色体核型组治疗前后SAM、SAH、HCY之间并无差异(P>0.05)。5.HgB治疗后变化数值与患者治疗前后HCY含量变化值呈正相关,两者相关系数R是0.33(P<0.05)；PLT治疗后变化数值与患者治疗前后HCY含量变化值呈正相关,两者相关系数R是0.35(P<0.01)。
结论：青黄散对SAM-SAH-HCY循环圈存在影响,由于青黄散对DNMT(?)表达量的影响导致了SAM向SAH的进一步代谢减弱,结果使SAM向DNA提供的甲基基团减少,降低了DNA的甲基化,从而改变MDS患者高甲基化状态起到治疗作用。
Part One To study effect of Qinghuang power treatment on DNMT1,DNMT3a,DNMT3b mRNA in MDS patients
Objective To study the effect of Qinghuang power on MDS patients'DNMT1, DNMT3a, DNMT3b mRNA expression and observe the correlations between Changes in peripheral blood cells and DNMT1, DNMT3a、DNMT3b. The Research Article focus on analysing Qinghuang power mechanism of therapeutic action.
Methods We analyses the changes of DNMT1, DNMT3a and DNMT3b mRNA relative quantitation which measured by a real-time quantitative PCR from30patients before and after treatment with Qinghuang powder. Peripheral blood cells were detected during the same period by hematology analyzer. After the test,the patients were divided into effective and ineffective groups according to clinical curative effects evaluation. The changes of DNMTs were observed respectively in the two groups. To discuss the correlations between DNMTs mRNA levels and changes in peripheral blood before and after the treatment. Maths model is built up to show the relationship of DNMTs mRNA levels and changes in peripheral blood using multiple linear regression analysis of experimental results,which can predict the change of blood cells by DNMTs mRNA content.
Results1.30cases of patients were evaluated by clinical curative effects evaluation,23patients were effective,7patients were ineffective, effective rate was76.67%;2Both Hgb and PLT were significantly increased effective group(p<0.05), nevertheless,the ineffective group was not(p>0.05).3.the level of DNMT1mRNA were decreased significantly in23effective cases compared with those before treatment (p<0.05), no significant changes were found in7ineffective cases (p>0.05)4. DNMT1DNMT3a DNMT3b mRNA relative content in valid group were lower than those in invalid group before treatment (P<0.05),The result was similar after treatment (P<0.05).5. The WBC change values demonstrated a negative correlation with DNMT3a mRNA relative quantitative logarithmic before treatment. their correlation coefficient is-0.41, The Hgb change values demonstrated a negative correlation both with DNMT1and with DNMT3a mRNA relative quantitative logarithmic before treatment. The correlation coefficient is-0.57and-0.67.The PLT change values demonstrated a negative correlation with DNMT1,DNMT3a and DNMT3b mRNA relative quantitative logarithmic before treatment.and also with DNMT3a mRNA. Correlation coefficient were-0.47,-0.37,-0.62and-0.41respectively.6.The three DNMTs mRNA factors affecting blood cells were analysed by multiple regression method and optimum equations were suggested for the main factor-Dnmtl mRNA relative quantitative logarithmic before treatment affecting Hgb and PLT.
Conclusion Qinghuang power mainly reflected on inhibition of DNMT1mRNA expression, It exert the therapeutic action on improving blood cells level by way of reducing methyltransferase activity and reducing methylation process from SAM to DNA.
Part Two To study effect of Qinghuang power treatment on S-adenosylmethionine meta-bolic circulation in MDS patients
Objective To study the effect of Qinghuang power on MDS patients' S-adenosylmethionine metabolic circulation and observe the correlations between changes in peripheral blood cells and SAM with its metabolic products. The Research Article focus on analysing Qinghuang power methylation pathway.
Methods We determined the serum contents of SAM,SAH,HCY measuring by Elisa from54patients before and after treatment with Qinghuang powder. Peripheral blood cells were detected during the same period by hematology analyzer. After the test,the patients were divided into effective and ineffective groups according to clinical curative effects evaluation and chromosomal karyotypes.The changes of SAM,SAH,HCY contents were observed respectively in the two groups. To discuss the correlations between changes of SAM,SAH,HCY contents and changes in peripheral blood before and after the treatment.
Results1.54cases of patients were evaluated by clinical curative effects evaluation,35patients were effective,19patients were ineffective, effective rate was64.81%;2Both Hgb and PLT were significantly increased in effective group (p<0.05), nevertheless,the ineffective group was not (p>0.05).3. No significant SAM content changes were observed in effective group (p>0.05).the level of SAH was decreased significantly after treatment (p <0.05). SAM:SAH ratio was increased after treatment (P<0.05);moreover,HCY contents rose in effective group (P<0.05), nevertheless, above data remained unchanged in19ineffective patients(P<0.05).4.54patients were split into three groups according to different chromosomal karyotypes.We compare the contents of SAM,SAH,HCY differences among three groups,and After statistics processing, the experiment result shows no evident differences among them (P>0.05).5. The Hgb change values demonstrated a positive correlation with HCY content before and after treatment. their correlation coefficient is0.33(P<0.05), The PLT change values demonstrated a positive correlation with HCY content before and after treatment.Their correlation coefficient is0.35(P<0.05)
Conclusion Qinghuang power influences SAM-SAH-HCY metabolic circulation.The inhibition of DNMT1mRNA induced by Qinghuang power causes metabolism weakness from SAM to SAH,which results reducing Methyl group transferred from SAM to DNA.
引文
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