寿胎丸影响反复自然流产模型小鼠妊娠结局的分子机制研究
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摘要
第一部分文献研究
目的：
通过文献研究,分别从中医和现代医学角度对反复自然流产的病因、病理机制及治疗方法进行阐述。
方法：
主要参考CNKI数据库、VIP数据库、PubMed数据库中收录的与反复自然流产相关的文献。
结果：
1.中医认为滑胎的病机主要有肾虚、心肾不交、气血两虚、血虚内热、肝血亏虚、血瘀等,治则治法主要有补肾、宁心安神、益气养血、清热养血、养血柔肝、活血化瘀等,临床治疗主要有分期治疗、辨证治疗及专方治疗等。
2.现代医学认为引起反复自然流产的因素主要有子宫异常、染色体异常、内分泌异常、微生物感染、免疫功能失调等,可通过激素、肝素/阿司匹林、静脉注射免疫球蛋白、淋巴细胞免疫、1α,25-二羟基维生素D3等治疗,但临床研究表明这些治疗方法均存有一定的风险及副作用。
结论：
中医认为脾肾虚损、气血不足、冲任损伤、胎元不固是滑胎的主要病机,治疗以补肾健脾、调养气血为主；现代医学认为反复自然流产主要与黄体功能不全和免疫功能失调有关,治疗以激素和免疫治疗为主。
第二部分实验研究
目的：
通过观察：①反复自然流产模型小鼠母胎界面SOCS1、SOCS2、SOCS3蛋白的表达差异；②寿胎丸对反复自然流产模型小鼠母胎界面SOCS1、SOCS3蛋白表达的影响,③寿胎丸对小鼠Th1高分化的CD4+T细胞SOCS1和SOCS3蛋白表达的影响,④寿胎丸对SOCS3蛋白表达相关的信号转导途径MAPK、NF-κB、JAK/STAT的影响,探讨寿胎丸治疗反复自然流产的分子生物学机制。
方法：
1.采用CBA/J×BALB/C建立正常妊娠小鼠模型,CBA/J×DBA/2建立反复自然流产小鼠模型,孕14d处死小鼠,取蜕膜和胎盘组织,通过免疫组化及Western blot分别检测SOCS1、SOCS2和SOCS3蛋白的表达。
2.将实验小鼠分为5组,分别为正常妊娠组、反复自然流产模型组及寿胎丸低、中、高剂量治疗组,给药14d后处死小鼠,计算小鼠胚胎吸收率,同时取蜕膜和胎盘组织,通过免疫组化及Western blot分别检测SOCS1和SOCS3蛋白的表达。
3.以OVA及IL-12刺激CD4+T细胞,建立Th1高分化的CD4+T细胞模型,按药物浓度和作用时间的不同将细胞模型分为A、B两组,其中A组分为空白血清对照组和寿胎丸低、中、高剂量药物血清组,B组分为0h、1h、2h、4h和8h组,采用Western blot方法分别检测SOCS1和SOCS3蛋白的表达。
4.将实验小鼠分为3组,分别为正常妊娠组、反复自然流产模型组及寿胎丸高剂量治疗组,给药14d后处死小鼠,取蜕膜和胎盘组织,分离CD4+T细胞,通过Springbio720点抗体芯片,分别检测各组小鼠母胎界面CD4+T细胞信号转导途径MAPK、NF-κB、JAK/STAT蛋白磷酸化水平。
结果：
1.与正常妊娠模型组相比,反复自然流产模型组小鼠的胚胎吸收率增高,差异有统计学意义(P<0.01),同时母胎界面SOCS1蛋白表达升高,差异有统计学意义(P<0.05),而SOCS3蛋白表达则降低,差异有统计学意义(P<0.01), SOCS2蛋白表达在两组间无显著差异(P>0.05)。
2.寿胎丸中、高剂量组均可降低反复自然流产小鼠胚胎吸收率,差异有统计学意义(P<0.01),且与正常妊娠组无显著差异(P>0.05)；寿胎丸低、中、高剂量组均可降低反复自然流产小鼠母胎界面SOCS1蛋白的表达,差异具有统计学意义(P<0.01),且与正常妊娠组无显著差别(P>0.05)；寿胎丸中、高剂量组可升高反复自然流产小鼠母胎界面SOCS3蛋白的表达,差异具有统计学意义(P<0.05,P<0.01),且高剂量组与正常妊娠组无显著差别(P>0.05)。
3.寿胎丸中剂量和高剂量药物血清可降低Th1高分化的CD4+T细胞SOCS1蛋白的表达,差异有统计学意义(P<0.01),同时高剂量药物血清还可提高其SOCS3蛋白表达水平,差异有统计学意义(P<0.01)；寿胎丸高剂量药物血清分别作用2、4、8h均可降低SOCS1蛋白的表达,差异有统计学意义(P<0.05),作用4h时达到最小值,高剂量药物血清分别作用2、4h可提高SOCS3蛋白表达水平,差异有统计学意义(P<0.05),作用4h时达到最大值。
4.寿胎丸可显著上调反复自然流产小鼠母胎界面CD4+T细胞MAPK信号转导途径的Rafl、A-Raf、Ask1、Mek1、Mek2、JKK1、ERK1、ERK2、c-fos、c-Jun和CREB等蛋白及JAK/STAT信号转导途径的STAT3、STAT6蛋白的磷酸化水平(≥1.5),同时显著下调MAPK信号转导途径的MEK6蛋白及NF-κB信号转导途径的IKKb蛋白的磷酸化水平(≤0.667且>0)。
结论：
通过ERK、JNK信号转导途径及STAT3、STAT6信号转导途径的活化而上调SOCS3的表达,进而调控Th细胞往Th2方向分化可能是寿胎丸治疗反复自然流产的分子生物学机制之一。
Part I Literature Research
Objective:
Described the cause, pathomechanism and treatment of recurrent spontaneous abortion from the perspective of Chinese medicine and modern medicine by literature research.
Methods:
Refer to the literatures about recurrent spontaneous abortion from the database of CNKI, VIP and PubMed.
Results:
1. In the viewpoint of Chinese medicine, the pathogenesis of recurrent abortion include kidney deficiency, non-interaction between the heart and kidney, deficiency of both QI and blood, blood deficiency with internal heat, hepatic blood deficiency and blood stasis. The therapeutic principles and methods of recurrent abortion include tonifing the kidney, calm the the heart to tranquilize, tonifing QI and nourishing blood, clearing heat and nourishing blood, nourishing blood and emolliating liver, activating blood and resolving stasis. The clinical therapy include stage treatment, differential treatment and special prescription.
2. In the viewpoint of modern medicine, the pathogenesis of recurrent spontaneous abortion include uterus abnormality,chromosomal abnormality, dyscrinism, infection of microorganism and disorder of immune function. The therapy of recurrent spontaneous abortion include hormonal therapy, heparin/ aspirin therapy, Intravenous immunoglobulin (IVIg) therapy, lymphocyte immunity and 1,25-dihydroxy vitamin D3 therapy. But the clinical research indicatd that some risks and side effects are presented in above-mentioned treatments.
Conclusion:
In the viewpoint of Chinese medicine, the main pathogenesis of recurrent abortion include deficiency of spleen-kidney or Qi-blood, damage of thoroughfare and conception vessels, and insecurity of foetus. Tonifying the kidney and spleen, regulating Qi and blood are the main treatments in Chinese medicine. In the viewpoint of modern medicine, recurrent spontaneous abortion are related with luteal phase defect or immune dysfunction, and the hormone/immune therapy are often used.
PartⅡExperimental Study
Objective:
To study molecular biological mechanism of Shoutaiwan treating RSA by observing①the different expression of the protein expression of SOCS1、SOCS2、SOCS3 in maternal-fetal interface of mice with normal pregnancy and recurrent spontaneous abortion(RSA);②the effects of Shoutaiwan on the protein expression of SOCS1 and SOCS3 in maternal-fetal interface of mice with RSA;③the effects of Shoutaiwan on the protein expression of SOCS1 and SOCS3 in mice CD4+T cell which had a differentiation bias toward Thl cell in vitro;④the effects of Shoutaiwan on the MAPK、NF-κB、JAK/STAT signal transduction pathway of CD4+T cells in maternal-fetal interface of mice with RSA.
Methods:
1. CBA/JxBALB/C and CBA/Jx DBA/2 were used as Normal pregnancy and RSA model respectively. The protein expressions of SOCS1、SOCS2 and SOCS3 in Decidual and placental tissues on day 14 of gestation were detected by western blotting and immunohistochemistry.
2. The mice were assigned to Normal pregnancy group、model group and low,middle,high dose group of Shoutaiwan. After 14 days of administration, The embryo resorption rate was counted,the protein expressions of SOCS1 and SOCS3 in mice decidual and placental tissues were detected by western blotting immunohistochemistry.
3. Thl differentiation bias of CD4+T cell model was established by the activiation of ovalbumin and IL-12.These model cells were randomly assigned to A part according to different concentration of drugs and B part according to different reaction times.A part included blank serum contrast group and low,middle,high dose Shoutaiwan-containing serum groups.B part included 0h,1h,2h,4h and 8h groups.The protein expression of SOCS1 and SOCS3 were detected respectively by western blotting.
4. The mice were assigned to Normal pregnancy group、model group and high dose group of Shoutaiwan. After 14 days of administration, the MAPK、NF- κB. JAK/STAT signal transduction pathway of CD4+T cells in mice decidual and placental tissues were detected by Springbio720 antibody microarrays.
Results:
1. Compared with normal pregnancy model mice, The models of embryo resorption rate are higher than the normal pregnancy group (P<0.01),the expression of SOCS1 had increased (P<0.05) and the expression of SOCS3 had significantly decreased in RSA model mice (P<0.01).The expression of SOCS2 had no obvious differences between normal pregnancy and RSA mice.
2. Middle and high groups of Shoutaiwan could decreased embryo resorption rate,and there were no obvious differences Compared with Normal pregnancy (P>0.05).All groups of Shoutaiwan could decreased the expression of SOCS1(P<0.01).There were no obvious differences between Normal pregnancy and all groups of Shoutaiwan(P>0.05). Middle and high groups of Shoutaiwan could increased the expression of SOCS3 (P<0.05). There were no obvious differences between Normal pregnancy and high dose group of Shoutaiwan(P>0.05).
3. Middle and high dose Shoutaiwan-containing serum could significantly decrease the expression of SOCS1(P<0.01).High dose Shoutaiwan-containing serum could significantly increase the expression of SOCS3(P<0.01).In addition,high dose Shoutaiwan-containing serum could significantly decrease the expression of SOCS1 respectivly at 2h,4h and 8h after treating (P<0.05),the peak was 4h.High dose Shoutaiwan-containing serum also significantly increase the expression of SOCS3 respectivly at 2h and 4h (P<0.05),the peak was 4h.
4. Shoutaiwan could increased the Phosphorylation level of Rafl、A-Raf、Ask1、Mek1、Mek2、JKK1、ERK2、ERK2、c-fos、c-Jun、CREB protein in the MAPK signal transduction pathway and STAT3、STAT6 protein in the STAT signal transduction pathway(≥1.5).At the same time,Shoutaiwan could decrease the Phosphorylation level of MEK6 protein in the MAPK signal transduction pathway and IKKb protein in the NF-κB signal transduction pathway(≤0.667and>0).
Conclusion:
The molecular biology mechanism in the therapy of RSA by Shoutaiwan maybe is that, Shoutaiwan enhance the expression of SOCS3 by activating the signal transduction pathway of ERK, JNK, STAT3 and STAT6, then the SOCS3 regulate the differentiation of Th cell toward Th2 cell to decrease the abortion rate.
目的：
通过文献研究,分别从中医和现代医学角度对反复自然流产的病因、病理机制及治疗方法进行阐述。
方法：
主要参考CNKI数据库、VIP数据库、PubMed数据库中收录的与反复自然流产相关的文献。
结果：
1.中医认为滑胎的病机主要有肾虚、心肾不交、气血两虚、血虚内热、肝血亏虚、血瘀等,治则治法主要有补肾、宁心安神、益气养血、清热养血、养血柔肝、活血化瘀等,临床治疗主要有分期治疗、辨证治疗及专方治疗等。
2.现代医学认为引起反复自然流产的因素主要有子宫异常、染色体异常、内分泌异常、微生物感染、免疫功能失调等,可通过激素、肝素/阿司匹林、静脉注射免疫球蛋白、淋巴细胞免疫、1α,25-二羟基维生素D3等治疗,但临床研究表明这些治疗方法均存有一定的风险及副作用。
结论：
中医认为脾肾虚损、气血不足、冲任损伤、胎元不固是滑胎的主要病机,治疗以补肾健脾、调养气血为主；现代医学认为反复自然流产主要与黄体功能不全和免疫功能失调有关,治疗以激素和免疫治疗为主。
第二部分实验研究
目的：
通过观察：①反复自然流产模型小鼠母胎界面SOCS1、SOCS2、SOCS3蛋白的表达差异；②寿胎丸对反复自然流产模型小鼠母胎界面SOCS1、SOCS3蛋白表达的影响,③寿胎丸对小鼠Th1高分化的CD4+T细胞SOCS1和SOCS3蛋白表达的影响,④寿胎丸对SOCS3蛋白表达相关的信号转导途径MAPK、NF-κB、JAK/STAT的影响,探讨寿胎丸治疗反复自然流产的分子生物学机制。
方法：
1.采用CBA/J×BALB/C建立正常妊娠小鼠模型,CBA/J×DBA/2建立反复自然流产小鼠模型,孕14d处死小鼠,取蜕膜和胎盘组织,通过免疫组化及Western blot分别检测SOCS1、SOCS2和SOCS3蛋白的表达。
2.将实验小鼠分为5组,分别为正常妊娠组、反复自然流产模型组及寿胎丸低、中、高剂量治疗组,给药14d后处死小鼠,计算小鼠胚胎吸收率,同时取蜕膜和胎盘组织,通过免疫组化及Western blot分别检测SOCS1和SOCS3蛋白的表达。
3.以OVA及IL-12刺激CD4+T细胞,建立Th1高分化的CD4+T细胞模型,按药物浓度和作用时间的不同将细胞模型分为A、B两组,其中A组分为空白血清对照组和寿胎丸低、中、高剂量药物血清组,B组分为0h、1h、2h、4h和8h组,采用Western blot方法分别检测SOCS1和SOCS3蛋白的表达。
4.将实验小鼠分为3组,分别为正常妊娠组、反复自然流产模型组及寿胎丸高剂量治疗组,给药14d后处死小鼠,取蜕膜和胎盘组织,分离CD4+T细胞,通过Springbio720点抗体芯片,分别检测各组小鼠母胎界面CD4+T细胞信号转导途径MAPK、NF-κB、JAK/STAT蛋白磷酸化水平。
结果：
1.与正常妊娠模型组相比,反复自然流产模型组小鼠的胚胎吸收率增高,差异有统计学意义(P<0.01),同时母胎界面SOCS1蛋白表达升高,差异有统计学意义(P<0.05),而SOCS3蛋白表达则降低,差异有统计学意义(P<0.01), SOCS2蛋白表达在两组间无显著差异(P>0.05)。
2.寿胎丸中、高剂量组均可降低反复自然流产小鼠胚胎吸收率,差异有统计学意义(P<0.01),且与正常妊娠组无显著差异(P>0.05)；寿胎丸低、中、高剂量组均可降低反复自然流产小鼠母胎界面SOCS1蛋白的表达,差异具有统计学意义(P<0.01),且与正常妊娠组无显著差别(P>0.05)；寿胎丸中、高剂量组可升高反复自然流产小鼠母胎界面SOCS3蛋白的表达,差异具有统计学意义(P<0.05,P<0.01),且高剂量组与正常妊娠组无显著差别(P>0.05)。
3.寿胎丸中剂量和高剂量药物血清可降低Th1高分化的CD4+T细胞SOCS1蛋白的表达,差异有统计学意义(P<0.01),同时高剂量药物血清还可提高其SOCS3蛋白表达水平,差异有统计学意义(P<0.01)；寿胎丸高剂量药物血清分别作用2、4、8h均可降低SOCS1蛋白的表达,差异有统计学意义(P<0.05),作用4h时达到最小值,高剂量药物血清分别作用2、4h可提高SOCS3蛋白表达水平,差异有统计学意义(P<0.05),作用4h时达到最大值。
4.寿胎丸可显著上调反复自然流产小鼠母胎界面CD4+T细胞MAPK信号转导途径的Rafl、A-Raf、Ask1、Mek1、Mek2、JKK1、ERK1、ERK2、c-fos、c-Jun和CREB等蛋白及JAK/STAT信号转导途径的STAT3、STAT6蛋白的磷酸化水平(≥1.5),同时显著下调MAPK信号转导途径的MEK6蛋白及NF-κB信号转导途径的IKKb蛋白的磷酸化水平(≤0.667且>0)。
结论：
通过ERK、JNK信号转导途径及STAT3、STAT6信号转导途径的活化而上调SOCS3的表达,进而调控Th细胞往Th2方向分化可能是寿胎丸治疗反复自然流产的分子生物学机制之一。
Part I Literature Research
Objective:
Described the cause, pathomechanism and treatment of recurrent spontaneous abortion from the perspective of Chinese medicine and modern medicine by literature research.
Methods:
Refer to the literatures about recurrent spontaneous abortion from the database of CNKI, VIP and PubMed.
Results:
1. In the viewpoint of Chinese medicine, the pathogenesis of recurrent abortion include kidney deficiency, non-interaction between the heart and kidney, deficiency of both QI and blood, blood deficiency with internal heat, hepatic blood deficiency and blood stasis. The therapeutic principles and methods of recurrent abortion include tonifing the kidney, calm the the heart to tranquilize, tonifing QI and nourishing blood, clearing heat and nourishing blood, nourishing blood and emolliating liver, activating blood and resolving stasis. The clinical therapy include stage treatment, differential treatment and special prescription.
2. In the viewpoint of modern medicine, the pathogenesis of recurrent spontaneous abortion include uterus abnormality,chromosomal abnormality, dyscrinism, infection of microorganism and disorder of immune function. The therapy of recurrent spontaneous abortion include hormonal therapy, heparin/ aspirin therapy, Intravenous immunoglobulin (IVIg) therapy, lymphocyte immunity and 1,25-dihydroxy vitamin D3 therapy. But the clinical research indicatd that some risks and side effects are presented in above-mentioned treatments.
Conclusion:
In the viewpoint of Chinese medicine, the main pathogenesis of recurrent abortion include deficiency of spleen-kidney or Qi-blood, damage of thoroughfare and conception vessels, and insecurity of foetus. Tonifying the kidney and spleen, regulating Qi and blood are the main treatments in Chinese medicine. In the viewpoint of modern medicine, recurrent spontaneous abortion are related with luteal phase defect or immune dysfunction, and the hormone/immune therapy are often used.
PartⅡExperimental Study
Objective:
To study molecular biological mechanism of Shoutaiwan treating RSA by observing①the different expression of the protein expression of SOCS1、SOCS2、SOCS3 in maternal-fetal interface of mice with normal pregnancy and recurrent spontaneous abortion(RSA);②the effects of Shoutaiwan on the protein expression of SOCS1 and SOCS3 in maternal-fetal interface of mice with RSA;③the effects of Shoutaiwan on the protein expression of SOCS1 and SOCS3 in mice CD4+T cell which had a differentiation bias toward Thl cell in vitro;④the effects of Shoutaiwan on the MAPK、NF-κB、JAK/STAT signal transduction pathway of CD4+T cells in maternal-fetal interface of mice with RSA.
Methods:
1. CBA/JxBALB/C and CBA/Jx DBA/2 were used as Normal pregnancy and RSA model respectively. The protein expressions of SOCS1、SOCS2 and SOCS3 in Decidual and placental tissues on day 14 of gestation were detected by western blotting and immunohistochemistry.
2. The mice were assigned to Normal pregnancy group、model group and low,middle,high dose group of Shoutaiwan. After 14 days of administration, The embryo resorption rate was counted,the protein expressions of SOCS1 and SOCS3 in mice decidual and placental tissues were detected by western blotting immunohistochemistry.
3. Thl differentiation bias of CD4+T cell model was established by the activiation of ovalbumin and IL-12.These model cells were randomly assigned to A part according to different concentration of drugs and B part according to different reaction times.A part included blank serum contrast group and low,middle,high dose Shoutaiwan-containing serum groups.B part included 0h,1h,2h,4h and 8h groups.The protein expression of SOCS1 and SOCS3 were detected respectively by western blotting.
4. The mice were assigned to Normal pregnancy group、model group and high dose group of Shoutaiwan. After 14 days of administration, the MAPK、NF- κB. JAK/STAT signal transduction pathway of CD4+T cells in mice decidual and placental tissues were detected by Springbio720 antibody microarrays.
Results:
1. Compared with normal pregnancy model mice, The models of embryo resorption rate are higher than the normal pregnancy group (P<0.01),the expression of SOCS1 had increased (P<0.05) and the expression of SOCS3 had significantly decreased in RSA model mice (P<0.01).The expression of SOCS2 had no obvious differences between normal pregnancy and RSA mice.
2. Middle and high groups of Shoutaiwan could decreased embryo resorption rate,and there were no obvious differences Compared with Normal pregnancy (P>0.05).All groups of Shoutaiwan could decreased the expression of SOCS1(P<0.01).There were no obvious differences between Normal pregnancy and all groups of Shoutaiwan(P>0.05). Middle and high groups of Shoutaiwan could increased the expression of SOCS3 (P<0.05). There were no obvious differences between Normal pregnancy and high dose group of Shoutaiwan(P>0.05).
3. Middle and high dose Shoutaiwan-containing serum could significantly decrease the expression of SOCS1(P<0.01).High dose Shoutaiwan-containing serum could significantly increase the expression of SOCS3(P<0.01).In addition,high dose Shoutaiwan-containing serum could significantly decrease the expression of SOCS1 respectivly at 2h,4h and 8h after treating (P<0.05),the peak was 4h.High dose Shoutaiwan-containing serum also significantly increase the expression of SOCS3 respectivly at 2h and 4h (P<0.05),the peak was 4h.
4. Shoutaiwan could increased the Phosphorylation level of Rafl、A-Raf、Ask1、Mek1、Mek2、JKK1、ERK2、ERK2、c-fos、c-Jun、CREB protein in the MAPK signal transduction pathway and STAT3、STAT6 protein in the STAT signal transduction pathway(≥1.5).At the same time,Shoutaiwan could decrease the Phosphorylation level of MEK6 protein in the MAPK signal transduction pathway and IKKb protein in the NF-κB signal transduction pathway(≤0.667and>0).
Conclusion:
The molecular biology mechanism in the therapy of RSA by Shoutaiwan maybe is that, Shoutaiwan enhance the expression of SOCS3 by activating the signal transduction pathway of ERK, JNK, STAT3 and STAT6, then the SOCS3 regulate the differentiation of Th cell toward Th2 cell to decrease the abortion rate.
引文
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