青黄散治疗骨髓增生异常综合征DNA磷硫酰化初探
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摘要
本论文从以下三方面阐述：
一、西苑医院血液科室青黄散治疗MDS疗效及疗效机理研究。
西苑医院血液科70年代开始以青黄散治疗各类恶性血液病,取得了良好疗效。尤其近十余年对骨髓增生异常综合征的治疗取得了显著成就。2000年以来青黄散+健脾补肾汤药为主治疗MDS病例共306例,总有效率79.5-82.3%,缓解率24.3%-26.5%；60%-70%病人外周血三系恢复正常,对各型MDS均有效,但疗效与FAB分型、IPSS危度及染色体异常有明显相关性。总体疗效优于现有的西医西药疗法。治疗过程中未出现阿扎胞苷、地西他宾治疗过程中常见的骨髓抑制、出血、感染等并发症,患者生活质量明显提高,生存期明显延长；而且患者花费极低(不及西医药治疗的1/10)。
疗效机制研究方面,深入研究了含砷中药治疗MDS的疗效机理。采用Affymetrix USA的GeneChip Human Promoter1.0Array基因芯片检测了MDS患者治疗前后的全基因甲基化状况。结果发现：未检出染色体核型异常的MDS患者发生甲基化的基因数量最多,三体8异常核型次之,其他异常核型患者发生甲基化的基因数量最少。结果表明：含砷中药治疗不能改变MDS患者已有的染色体异常,但异常增高的甲基化显著减低,含砷中药治疗的主要作用机理是去甲基化。治疗后去甲基化的基因主要包括多细胞生命发育生物学途径、转录调控生物学途径、细胞凋亡生物学途径、信号转导生物学途径。
二、MDS治疗及疗效机制研究展望
既往研究中问题及展望：1.虽然我们已证实含砷中药治疗MDS的主要作用机理是去甲基化,但其去甲基化机理仍需进一步研究。研究证明砷剂解毒代谢过程中竞争甲基,从而使MDS过度甲基化基因去甲基化而发挥治疗作用。我们推测砷剂去甲基化机理极可能是竞争甲基而表现去甲基化作用。但中药砷剂去甲基化有无靶点特异性?还是无靶点特异性的泛去甲基化?需要进一步研究阐明。还有甲基化表现为具有一定的可逆性,甲基化做为生物体生理性保护机制,药物干预后经过一定时间去甲基化基因重新恢复甲基化状态,青黄散治疗有无这种现象,也需要进一步阐明。2.血砷浓度差异性问题。我们前期研究中也发现血砷浓度个体差异性大,砷的吸收和代谢存在个体差异性。研究中发现病人服用同样剂量的青黄散而全血砷浓度不同,说明砷剂的胃肠吸收存在明显的个体差异性。因此有必要开展个体化血砷浓度检测和疗效关系的研究,减少因胃肠吸收少血砷浓度不能达到有效浓度的病人,提高MDS临床疗效。另外其他研究机构正在开展纳米雄黄研究,结果表明纳米雄黄的吸收效率,峰浓度明显高于水飞雄黄组,值得进一步探讨纳米雄黄应用。降低胃肠道副作用,以及有效利用中药材等方面具有积极意义。3.展望：既往的MDS疗效机理研究中已证明青黄散治疗MDS疗效机制为雄黄在体内代谢过程中产生的去甲基化效应。我们已筛选出含砷中药治疗前MDS病人呈现高甲基化而治疗后去甲基化的13个基因。探索研究这些基因甲基化成因,提出预防、干预措施,从根源上减低和预防MDS的发生。此次磷硫酰化机制研究也是在前期表观遗传学研究基础上的进一步探索,是一项为阐明青黄散疗效机制的又一次尝试。
三、青黄散治疗后MDS患者骨髓细胞磷硫酰化初探。
研究背景：组成DNA的元素碳(C)、氢(H)、氧(O)、氮(N)、磷(P)被称为生命必需元素。DNA只含CHONP五种元素吗?科学家在研究生物体DNA分子过程中发现除了碳、氢、氧、氮、磷五种元素外另一种组成元素,即为硫元素。该发现源于磷硫酰化研究中,磷硫酰化修饰就是DNA的磷酸二酯键发生了构象变化,即磷酸二酯键羟基上的氧原子被硫原子替代形成RP构象的硫代磷酸二酯键。这是首次在DNA骨架上发现的新的修饰。
2005年,美国科学院院刊(PNAS)发表了一篇以上海交通大学王连荣教授为第一作者,陈实教授和彼得·帝丹教授为共同通讯作者的论文：“DNA磷硫酰化修饰在细菌基因组中广泛分布且量化存在”,这对于DNA硫修饰研究来说是一次重大突破,从基因层面阐述了硫酰化机制。
DNA降解表型(DNA degradation, Dnd)最早发现于变铅青链霉菌研究中,电泳过程中发现变铅青链霉菌的染色体出现降解现象,不再是清晰的DNA条带。研究证实,这是因为DNA上出现了复制后修饰,这种修饰使在凝胶中电泳时的DNA容易受到阳极的Tris过酸衍生物位点特异性攻击而导致双链切割反应。这种异常的修饰是一种DNA的硫修饰,是与dnd基因簇有关的。通过喂养放射性物质35S,在具有dnd同源基因簇/Dnd表型的变铅青链霉菌66,阿维链霉菌NRRL8165和荧光假单胞菌Pfo-1的DNA上检测到了具有放射性的硫信号,显示出除碳、氮、氢、磷和氧五种元素之外,DNA的组成中存在第六种元素--硫。
研究目的：众所周知自然界多种药物如博莱霉素等抗生素会对DNA造成损伤断裂；而磷酸二甲酯、肼也会对DNA进行特异性切割；含铁离子的EDTA作为寡聚核苷酸配基也对DNA有位点特异性切割。青黄散作为硫化砷制剂,对血液恶性肿瘤细胞表现出抑制,诱导凋亡和去甲基化作用。那么对DNA双链结构有无影响?硫元素可否掺入DNA骨架?有无存在DNA结构的硫酰化修饰?这就是本课题研究的目的。
研究方法：抽取符合纳入标准的MDS患者骨髓2ml。首先分离、纯化DNA,制备琼脂糖包埋的DNA样品。利用BIO-RAD CHEF-DRⅢ System脉冲场电泳检测DNA降解表型。
研究结果：将10例琼脂糖包埋的骨髓细胞DNA利用BIO-RAD CHEF-DR Ⅲ System脉冲电泳进行分析,结果发见标本DNA完好,在Tris缓冲液下未出现DNA降解现象。
研究结论：利用BIO-RAD CHEF-DRⅢ System脉冲电泳对琼脂糖包埋的骨髓单个核细胞DNA进行分析,结果未发现DNA降解现象。说明青黄散治疗有效患者骨髓细胞DNA骨架中并没有存在磷硫酰化修饰现象。从另一角度也说明青黄散疗效机制不通过硫修饰系统。
本文的创新点在于：哺乳动物DNA磷硫酰化研究国内外未见报道,本课题探索性的研究长期硫化砷干预后人类DNA磷硫酰化修饰。
1. The study on the mechanism of Qing-Huang powder in cure MDS of Xiyuan Hospital
We gained curative effect, especially MDS. Since2000, Qing-Huang powder have treated MDS patients for a total of306cases. The total efficiency is79.5%-82.3%, remission rate is24.3%-26.5%. For instance, Professor Marou has cured55MDS patients with Qing-Huang powder and reinforcing kidney herbs,41patients (74.5%) have effectiveness. Professor Marou using Qing-Huang powder、reinforcing kidney herbs and androgen cured106MDS patients,44(41.51%)of them are excellence,53(50%) of them are in stable,9(8.49%) of them are invalid. There is non-statistic difference on treatment respond of Qing-Huang powder towards different cytogenetics. The overall effect is better than the western medicine therapy, the quality of patients life is significantly improved.
2. The prospect of curative effect mechanism in treating MDS
Although we have confirmed that the main effect of arsenic traditional Chinese medicine in the treatment of MDS is demethylation, but the mechanism of demethylation still needs further study. The problem of the differences of the concentration of arsenic in blood. Our previous study also found that the concentration of arsenic in blood has great individual difference, absorption and metabolism of arsenic in individual differences. So it is necessary to study the relationship between individual blood arsenic concentration detection and curative effect, improve clinical efficacy.
The study on the phosphorothioation mechanism is a further explore based on the early stage of genetics research. It is a tries to clarify the therapeutic mechanism of Qinghuang powder.
3. The study on DNA phosphorothioate of Qinghuang powder in treating MDS.
It is believed that the elements of DNA:Carbon(C)、Hydrogen(H)、Oxygen(O)、 Nitrogen(N)、Phosphorus(P), are the five indispensable of the structures of the life. However, there is the sixth element--Sulfur(S).This is the phosphorothioate on phosphodiester bond of DNA. The element S substitute the O on hydroxyl group and to become phosphorothioic acid bond。 This is the first modification on the DNA structure besides the modificate on nucleic acid base. The PNAS published an article on2005--"DNA phosphorothioate is generally distribute on Bacterial Genome and quantifying".The authors are professors Lianrongwang and Shicheng. This is the importance progress in Sulfur modification on DNA--the element S incorporate in DNA structure.
DNA phosphorothioate modification exists in a wide variety of bacterial species. DNA degradation is found in Streptomyces lividans the first. The chromosomes of Streptomyces lividans is degradation in electrophoresis. In research,this is result of abnormal modification, which lead to DNA double-stranded cutting reaction in electrophoresis。Resently, some researchers found this abnormal modification is DNA modification, which is related to Dnd gene clusters.
In curative effect mechanism, Professor Marou found that after6months' treatment by Qinghuang Powder, the MDS patients have only75different methylation genes with18functions by Go-analysis method, including blood coagulation, regulation of mitosis, cell-cell adhesion, protein transport, and so on. Compared to pre-treatment, the signal transduction and DNA repair have disappeared. There are21different methylation genes with8pathway by Pathway-analysis method, including Glycolysis/Gluconeogenesis, Influenza A, kidney disease, gastrointestinal disease pathways, and so on. Compared to pre-treatment, the pathways in cancer, chemokine signaling pathway, cell adhesion pathway, MAPK signaling pathway, and calcium signaling pathway have disappeared.
Purpose:It's all known that many drags like bleomycins can damage DNA; dimethylster and hydrazine can also make specificity cutting to DNA, as well as EDTA including ferriion. Qinghuang Powder, as yellow arsenic preparation, has well effect inhibition or apoptosis on cells of blood cancer. Does it affect duplex structure? Can S mix into DNA bone? Dose there exist the DNA phosphorothioate modification? They are the purpose of this study.
Methods:Draw off2ml bone marrow of MDS patient, which accord with internalize standard. Chorisis and purify DNA, then prepare DNA sample of Sepharose embedding. Take advantage of BIO-RAD CHEF-DFⅢ System to pulse electrophoresis check degradation phenotype of DNA.
Results:molecular weight standard samples are in M track, test specimen DNA is from N1to N10.It's shown that DNA sample is fine, there is no DNA degradation in Tris buffer.
Conclusion:Take advantage of BIO-RAD CHEF-DFⅢ System to pulse electrophoresis to analyze DNA of bone marrow in sepharose, DNA degradation has not been found, which suggest that there is no DNA phosphorothioate modification after a long time interference to patient's marrow cells DNA bone by Qinghuang Powder.
New ideas:there is no report about mammals' DNA phosphorothioate research, neither home nor broad. This study focuses on DNA phosphorothioate modification after long-term yellow arsenic interference.
一、西苑医院血液科室青黄散治疗MDS疗效及疗效机理研究。
西苑医院血液科70年代开始以青黄散治疗各类恶性血液病,取得了良好疗效。尤其近十余年对骨髓增生异常综合征的治疗取得了显著成就。2000年以来青黄散+健脾补肾汤药为主治疗MDS病例共306例,总有效率79.5-82.3%,缓解率24.3%-26.5%；60%-70%病人外周血三系恢复正常,对各型MDS均有效,但疗效与FAB分型、IPSS危度及染色体异常有明显相关性。总体疗效优于现有的西医西药疗法。治疗过程中未出现阿扎胞苷、地西他宾治疗过程中常见的骨髓抑制、出血、感染等并发症,患者生活质量明显提高,生存期明显延长；而且患者花费极低(不及西医药治疗的1/10)。
疗效机制研究方面,深入研究了含砷中药治疗MDS的疗效机理。采用Affymetrix USA的GeneChip Human Promoter1.0Array基因芯片检测了MDS患者治疗前后的全基因甲基化状况。结果发现：未检出染色体核型异常的MDS患者发生甲基化的基因数量最多,三体8异常核型次之,其他异常核型患者发生甲基化的基因数量最少。结果表明：含砷中药治疗不能改变MDS患者已有的染色体异常,但异常增高的甲基化显著减低,含砷中药治疗的主要作用机理是去甲基化。治疗后去甲基化的基因主要包括多细胞生命发育生物学途径、转录调控生物学途径、细胞凋亡生物学途径、信号转导生物学途径。
二、MDS治疗及疗效机制研究展望
既往研究中问题及展望：1.虽然我们已证实含砷中药治疗MDS的主要作用机理是去甲基化,但其去甲基化机理仍需进一步研究。研究证明砷剂解毒代谢过程中竞争甲基,从而使MDS过度甲基化基因去甲基化而发挥治疗作用。我们推测砷剂去甲基化机理极可能是竞争甲基而表现去甲基化作用。但中药砷剂去甲基化有无靶点特异性?还是无靶点特异性的泛去甲基化?需要进一步研究阐明。还有甲基化表现为具有一定的可逆性,甲基化做为生物体生理性保护机制,药物干预后经过一定时间去甲基化基因重新恢复甲基化状态,青黄散治疗有无这种现象,也需要进一步阐明。2.血砷浓度差异性问题。我们前期研究中也发现血砷浓度个体差异性大,砷的吸收和代谢存在个体差异性。研究中发现病人服用同样剂量的青黄散而全血砷浓度不同,说明砷剂的胃肠吸收存在明显的个体差异性。因此有必要开展个体化血砷浓度检测和疗效关系的研究,减少因胃肠吸收少血砷浓度不能达到有效浓度的病人,提高MDS临床疗效。另外其他研究机构正在开展纳米雄黄研究,结果表明纳米雄黄的吸收效率,峰浓度明显高于水飞雄黄组,值得进一步探讨纳米雄黄应用。降低胃肠道副作用,以及有效利用中药材等方面具有积极意义。3.展望：既往的MDS疗效机理研究中已证明青黄散治疗MDS疗效机制为雄黄在体内代谢过程中产生的去甲基化效应。我们已筛选出含砷中药治疗前MDS病人呈现高甲基化而治疗后去甲基化的13个基因。探索研究这些基因甲基化成因,提出预防、干预措施,从根源上减低和预防MDS的发生。此次磷硫酰化机制研究也是在前期表观遗传学研究基础上的进一步探索,是一项为阐明青黄散疗效机制的又一次尝试。
三、青黄散治疗后MDS患者骨髓细胞磷硫酰化初探。
研究背景：组成DNA的元素碳(C)、氢(H)、氧(O)、氮(N)、磷(P)被称为生命必需元素。DNA只含CHONP五种元素吗?科学家在研究生物体DNA分子过程中发现除了碳、氢、氧、氮、磷五种元素外另一种组成元素,即为硫元素。该发现源于磷硫酰化研究中,磷硫酰化修饰就是DNA的磷酸二酯键发生了构象变化,即磷酸二酯键羟基上的氧原子被硫原子替代形成RP构象的硫代磷酸二酯键。这是首次在DNA骨架上发现的新的修饰。
2005年,美国科学院院刊(PNAS)发表了一篇以上海交通大学王连荣教授为第一作者,陈实教授和彼得·帝丹教授为共同通讯作者的论文：“DNA磷硫酰化修饰在细菌基因组中广泛分布且量化存在”,这对于DNA硫修饰研究来说是一次重大突破,从基因层面阐述了硫酰化机制。
DNA降解表型(DNA degradation, Dnd)最早发现于变铅青链霉菌研究中,电泳过程中发现变铅青链霉菌的染色体出现降解现象,不再是清晰的DNA条带。研究证实,这是因为DNA上出现了复制后修饰,这种修饰使在凝胶中电泳时的DNA容易受到阳极的Tris过酸衍生物位点特异性攻击而导致双链切割反应。这种异常的修饰是一种DNA的硫修饰,是与dnd基因簇有关的。通过喂养放射性物质35S,在具有dnd同源基因簇/Dnd表型的变铅青链霉菌66,阿维链霉菌NRRL8165和荧光假单胞菌Pfo-1的DNA上检测到了具有放射性的硫信号,显示出除碳、氮、氢、磷和氧五种元素之外,DNA的组成中存在第六种元素--硫。
研究目的：众所周知自然界多种药物如博莱霉素等抗生素会对DNA造成损伤断裂；而磷酸二甲酯、肼也会对DNA进行特异性切割；含铁离子的EDTA作为寡聚核苷酸配基也对DNA有位点特异性切割。青黄散作为硫化砷制剂,对血液恶性肿瘤细胞表现出抑制,诱导凋亡和去甲基化作用。那么对DNA双链结构有无影响?硫元素可否掺入DNA骨架?有无存在DNA结构的硫酰化修饰?这就是本课题研究的目的。
研究方法：抽取符合纳入标准的MDS患者骨髓2ml。首先分离、纯化DNA,制备琼脂糖包埋的DNA样品。利用BIO-RAD CHEF-DRⅢ System脉冲场电泳检测DNA降解表型。
研究结果：将10例琼脂糖包埋的骨髓细胞DNA利用BIO-RAD CHEF-DR Ⅲ System脉冲电泳进行分析,结果发见标本DNA完好,在Tris缓冲液下未出现DNA降解现象。
研究结论：利用BIO-RAD CHEF-DRⅢ System脉冲电泳对琼脂糖包埋的骨髓单个核细胞DNA进行分析,结果未发现DNA降解现象。说明青黄散治疗有效患者骨髓细胞DNA骨架中并没有存在磷硫酰化修饰现象。从另一角度也说明青黄散疗效机制不通过硫修饰系统。
本文的创新点在于：哺乳动物DNA磷硫酰化研究国内外未见报道,本课题探索性的研究长期硫化砷干预后人类DNA磷硫酰化修饰。
1. The study on the mechanism of Qing-Huang powder in cure MDS of Xiyuan Hospital
We gained curative effect, especially MDS. Since2000, Qing-Huang powder have treated MDS patients for a total of306cases. The total efficiency is79.5%-82.3%, remission rate is24.3%-26.5%. For instance, Professor Marou has cured55MDS patients with Qing-Huang powder and reinforcing kidney herbs,41patients (74.5%) have effectiveness. Professor Marou using Qing-Huang powder、reinforcing kidney herbs and androgen cured106MDS patients,44(41.51%)of them are excellence,53(50%) of them are in stable,9(8.49%) of them are invalid. There is non-statistic difference on treatment respond of Qing-Huang powder towards different cytogenetics. The overall effect is better than the western medicine therapy, the quality of patients life is significantly improved.
2. The prospect of curative effect mechanism in treating MDS
Although we have confirmed that the main effect of arsenic traditional Chinese medicine in the treatment of MDS is demethylation, but the mechanism of demethylation still needs further study. The problem of the differences of the concentration of arsenic in blood. Our previous study also found that the concentration of arsenic in blood has great individual difference, absorption and metabolism of arsenic in individual differences. So it is necessary to study the relationship between individual blood arsenic concentration detection and curative effect, improve clinical efficacy.
The study on the phosphorothioation mechanism is a further explore based on the early stage of genetics research. It is a tries to clarify the therapeutic mechanism of Qinghuang powder.
3. The study on DNA phosphorothioate of Qinghuang powder in treating MDS.
It is believed that the elements of DNA:Carbon(C)、Hydrogen(H)、Oxygen(O)、 Nitrogen(N)、Phosphorus(P), are the five indispensable of the structures of the life. However, there is the sixth element--Sulfur(S).This is the phosphorothioate on phosphodiester bond of DNA. The element S substitute the O on hydroxyl group and to become phosphorothioic acid bond。 This is the first modification on the DNA structure besides the modificate on nucleic acid base. The PNAS published an article on2005--"DNA phosphorothioate is generally distribute on Bacterial Genome and quantifying".The authors are professors Lianrongwang and Shicheng. This is the importance progress in Sulfur modification on DNA--the element S incorporate in DNA structure.
DNA phosphorothioate modification exists in a wide variety of bacterial species. DNA degradation is found in Streptomyces lividans the first. The chromosomes of Streptomyces lividans is degradation in electrophoresis. In research,this is result of abnormal modification, which lead to DNA double-stranded cutting reaction in electrophoresis。Resently, some researchers found this abnormal modification is DNA modification, which is related to Dnd gene clusters.
In curative effect mechanism, Professor Marou found that after6months' treatment by Qinghuang Powder, the MDS patients have only75different methylation genes with18functions by Go-analysis method, including blood coagulation, regulation of mitosis, cell-cell adhesion, protein transport, and so on. Compared to pre-treatment, the signal transduction and DNA repair have disappeared. There are21different methylation genes with8pathway by Pathway-analysis method, including Glycolysis/Gluconeogenesis, Influenza A, kidney disease, gastrointestinal disease pathways, and so on. Compared to pre-treatment, the pathways in cancer, chemokine signaling pathway, cell adhesion pathway, MAPK signaling pathway, and calcium signaling pathway have disappeared.
Purpose:It's all known that many drags like bleomycins can damage DNA; dimethylster and hydrazine can also make specificity cutting to DNA, as well as EDTA including ferriion. Qinghuang Powder, as yellow arsenic preparation, has well effect inhibition or apoptosis on cells of blood cancer. Does it affect duplex structure? Can S mix into DNA bone? Dose there exist the DNA phosphorothioate modification? They are the purpose of this study.
Methods:Draw off2ml bone marrow of MDS patient, which accord with internalize standard. Chorisis and purify DNA, then prepare DNA sample of Sepharose embedding. Take advantage of BIO-RAD CHEF-DFⅢ System to pulse electrophoresis check degradation phenotype of DNA.
Results:molecular weight standard samples are in M track, test specimen DNA is from N1to N10.It's shown that DNA sample is fine, there is no DNA degradation in Tris buffer.
Conclusion:Take advantage of BIO-RAD CHEF-DFⅢ System to pulse electrophoresis to analyze DNA of bone marrow in sepharose, DNA degradation has not been found, which suggest that there is no DNA phosphorothioate modification after a long time interference to patient's marrow cells DNA bone by Qinghuang Powder.
New ideas:there is no report about mammals' DNA phosphorothioate research, neither home nor broad. This study focuses on DNA phosphorothioate modification after long-term yellow arsenic interference.
引文
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4.刘峰等.益髓青黄散治疗骨髓增生异常综合征36例.中医杂志.2011,52(3)：241：242.
5. Shuzhen S, Rou M (Correspondence), Xiaomei H, Xiao-Hong Y, Yong-Gang X, Hongzhi W, Xiu-Peng Y:Karyotype and DNA-Methylation Responses in Myelo-dysplastic Syndromes following Treatment with Traditional Chinese Formula Con- taining Arsenic. Evid Based Complement Alternat Med.2012;2012:969476. doi:10.1155/2012/969476.Epub 2012 Oct 16.
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8徐述,麻柔指导.化瘀补肾法治疗骨髓增生异常综合征的临床和实验研究.中国中医科学院2004级博士研究生学位论文,北京：2007.
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10高飞 杨晓红 麻柔 许勇钢：青黄散合健脾补肾中药对MDS患者活化T细胞的影响。中国中西医结合杂志,33(4)：443-447.
11高飞,麻柔指导.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.中国中医科学院2010级博士研究生学位论文,北京：2013
12高飞,,麻柔指导.青黄散影响MDS患者骨髓单个核细胞内HIF-la的研究(待发表)
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