补髓生血颗粒对慢性再生障碍性贫血患者信号转导MAPK通路及相关细胞因子的影响
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摘要
目的:观察补髓生血颗粒对慢性再生障碍性贫血(CAA)的临床疗效,探索补髓生血颗粒对CAA患者骨髓基质细胞黏附信号转导MAPK通路的影响以及相关细胞因子的研究。
方法:将124例CAA患者分为两组,试验组61例,使用补髓生血颗粒治疗。对照组63例,使用再造生血片治疗。3个月为1个疗程,6个月后对两组患者进行相关临床疗效比较。采用Westernblot法检测CAA患者治疗前后骨髓基质细胞MAPK信号转导通路中ERK1/2、P38、JNK蛋白磷酸化水平。采用RT-PCR法检测CAA患者治疗前后骨髓基质细胞中细胞因子bFGF及其受体bFGFR的mRNA表达变化。
结果:1.补髓生血颗粒疗效确切,其疗效优于再造生血片,两者比较有显著性差异(P<0.05);2.CAA肾阳虚型疗效优于肾阴虚型(P<0.05);3.CAA患者骨髓基质细胞P-ERK1/2蛋白表达水平低于正常组(P<0.05),P-JNK与P-P38蛋白表达水平高于正常组(P<0.05);治疗前肾阳虚型患者P-ERK1/2蛋白表达水平高于肾阴虚型(P<0.05),P-JNK表达水平低于肾阴虚型(P<0.05),补髓生血颗粒可以调整三种蛋白的异常表达,与治疗前比较(P均<0.05);4.CAA患者骨髓基质细胞bFGF与bFGFR的mRNA表达水平明显降低(P<0.05),经补髓生血颗粒治疗后bFGF与bFGFR的mRNA表达水平有所提高(P均<0.05),并且治疗后肾阳虚型与肾阴虚型比较具有显著性差异(P<0.05)。
结论:1.补髓生血颗粒具有较好的临床疗效,是治疗CAA的有效药物。2.CAA患者骨髓基质细胞造血粘附信号转导通路中P-ERK1/2的表达水平低于正常组,P-JNK与P-P38的表达水平明显高于正常组,这些可能是骨髓造血微环境粘附功能异常的原因之一,为CAA发病机制研究提供了分子生物学依据;3.补髓生血颗粒可以明显提升P-ERK1/2的表达,抑制基质细胞凋亡,从而改善了骨髓造血微环境,使细胞的增殖、分化与存活恢复正常。同时能降低P-JNK、P-P38蛋白表达水平,从而改善造血干/祖细胞的归巢、移行,增强造血粘附信号转导,达到治疗CAA的效果;4.P-ERK1/2在肾阳虚型患者中表达水平高于肾阴虚型,P-JNK在肾阳型患者中蛋白表达水平低于肾阴虚型,这些结果为CAA中医辨证分型的客观化提供参考;5.本研究提示,补髓生血颗粒对细胞因子bFGF与bFGFR的mRNA表达水平有调节作用,通过调控CAA骨髓基质细胞的增殖和定向分化以及促进骨髓新生血管的形成改善了造血微环境,促进骨髓造血功能的恢复;6.肾阳虚型患者骨髓基质细胞中的P-ERK1/2、P-JNK的蛋白表达异常和bFGF及bFGFRmRNA表达异常较肾阴虚型患者的更易得到纠正,这也可能是肾阳虚型患者的疗效优于肾阴虚型患者的机理之一。
Objective: To observe the clinical efficacy of Busui Shengxue Granule (BSSXG) in chronic aplastic anemia (CAA) and disscuss the differences in expression of signal transduction pathway MAPK before and after treatment. We observe the phosphorylation including ERK1/2, JNK, P38 and the expression of mRNA in bFGF and bFGFR.
Methods: 124 cases of CAA were divided into two groups randomly.There are 61 cases who were used by BSSXG in experimental group,and 63 cases treatmented by Zaizaoshengxue Tablet in control group. The protein expression of enzymes P-ERK1/2, P-JNK, P-P38 of cultured bone marrow stromal cells were measured by Western blot and the mRNA expression of bFGF and bFGFR were measured by RT-PCR.
Results: 1.The effects of BSSXG was superior to that of Zaizaoshengxue Tablet (p<0.05).2.The effect of Kidney-Yang deficiency type was superior to that of Kidney-Yin deficiency type(p<0.05). 3.The expression level of P-ERK1/2 in CAA patients were lower than that in normal group(P<0.05). P-JNK and P-P38 protein levels were higher than that of normal group (P<0.05), and the level of P-ERK1/2 in Kidney-yang deficient patients higher than that of Kidney-yin deficiency (P <0.05), P-JNK lower than the Kidney-yin deficiency (P <0.05), BSSXG can adjusted the abnormal expression of three protein. 4. The mRNA expression of bFGF and bFGFR of CAA lower than that of normal group (P<0.05). After treatment BSSXG made the mRNA expression of bFGF and bFGFR levels increased (P <0.05), and the effect of Kidney-Yin deficiency had a significant difference with Kidney -Yang dificiency (P <0.05).
Conclusion: 1. BSSXG have better clinical efficacy, it is an effective drug for treatment of CAA. 2. The lower expression of P-ERK1/2 and the higher expression of P-JNK and P-P38 in CAA bone marrow stomal may be one of the mechanisms of bone marrow microenvironment environmental adhesion dysfunction. 3.BSSXG can significantly enhance the P-ERK1/2 expression and inhibite stromal cell apoptosis, improve the bone marrow micro-environment for cell proliferation, differentiation and survival returned to normal. Meanwhile, reduction of P-JNK, P-P38 protein levels can improve the hematopoietic stem cell / progenitor cell homing, migration, and enhance the adhesion of hematopoietic signal transduction. 4.P-ERK1/2 expression in the kidney-Yang deficiency was higher than that in patients with Kidney-Yin deficiency, P-JNK in the kidney-Yang type protein level in patients lower than kidney-Yin deficiency. These results may make references for the TCM treatments of CAA. 5.This study suggest that BSSXG can reulate the bFGF and bFGFR expression levels. This can proliferate and directionally differentiate and promote bone marrow angiogenesis, improve the hematopoietic microenvironment. It also can conclude that the mRNA of bFGF and bFGFR of kidney-Yang deficiency can be corrected better than that of in kidney-Yin deficiency.
方法:将124例CAA患者分为两组,试验组61例,使用补髓生血颗粒治疗。对照组63例,使用再造生血片治疗。3个月为1个疗程,6个月后对两组患者进行相关临床疗效比较。采用Westernblot法检测CAA患者治疗前后骨髓基质细胞MAPK信号转导通路中ERK1/2、P38、JNK蛋白磷酸化水平。采用RT-PCR法检测CAA患者治疗前后骨髓基质细胞中细胞因子bFGF及其受体bFGFR的mRNA表达变化。
结果:1.补髓生血颗粒疗效确切,其疗效优于再造生血片,两者比较有显著性差异(P<0.05);2.CAA肾阳虚型疗效优于肾阴虚型(P<0.05);3.CAA患者骨髓基质细胞P-ERK1/2蛋白表达水平低于正常组(P<0.05),P-JNK与P-P38蛋白表达水平高于正常组(P<0.05);治疗前肾阳虚型患者P-ERK1/2蛋白表达水平高于肾阴虚型(P<0.05),P-JNK表达水平低于肾阴虚型(P<0.05),补髓生血颗粒可以调整三种蛋白的异常表达,与治疗前比较(P均<0.05);4.CAA患者骨髓基质细胞bFGF与bFGFR的mRNA表达水平明显降低(P<0.05),经补髓生血颗粒治疗后bFGF与bFGFR的mRNA表达水平有所提高(P均<0.05),并且治疗后肾阳虚型与肾阴虚型比较具有显著性差异(P<0.05)。
结论:1.补髓生血颗粒具有较好的临床疗效,是治疗CAA的有效药物。2.CAA患者骨髓基质细胞造血粘附信号转导通路中P-ERK1/2的表达水平低于正常组,P-JNK与P-P38的表达水平明显高于正常组,这些可能是骨髓造血微环境粘附功能异常的原因之一,为CAA发病机制研究提供了分子生物学依据;3.补髓生血颗粒可以明显提升P-ERK1/2的表达,抑制基质细胞凋亡,从而改善了骨髓造血微环境,使细胞的增殖、分化与存活恢复正常。同时能降低P-JNK、P-P38蛋白表达水平,从而改善造血干/祖细胞的归巢、移行,增强造血粘附信号转导,达到治疗CAA的效果;4.P-ERK1/2在肾阳虚型患者中表达水平高于肾阴虚型,P-JNK在肾阳型患者中蛋白表达水平低于肾阴虚型,这些结果为CAA中医辨证分型的客观化提供参考;5.本研究提示,补髓生血颗粒对细胞因子bFGF与bFGFR的mRNA表达水平有调节作用,通过调控CAA骨髓基质细胞的增殖和定向分化以及促进骨髓新生血管的形成改善了造血微环境,促进骨髓造血功能的恢复;6.肾阳虚型患者骨髓基质细胞中的P-ERK1/2、P-JNK的蛋白表达异常和bFGF及bFGFRmRNA表达异常较肾阴虚型患者的更易得到纠正,这也可能是肾阳虚型患者的疗效优于肾阴虚型患者的机理之一。
Objective: To observe the clinical efficacy of Busui Shengxue Granule (BSSXG) in chronic aplastic anemia (CAA) and disscuss the differences in expression of signal transduction pathway MAPK before and after treatment. We observe the phosphorylation including ERK1/2, JNK, P38 and the expression of mRNA in bFGF and bFGFR.
Methods: 124 cases of CAA were divided into two groups randomly.There are 61 cases who were used by BSSXG in experimental group,and 63 cases treatmented by Zaizaoshengxue Tablet in control group. The protein expression of enzymes P-ERK1/2, P-JNK, P-P38 of cultured bone marrow stromal cells were measured by Western blot and the mRNA expression of bFGF and bFGFR were measured by RT-PCR.
Results: 1.The effects of BSSXG was superior to that of Zaizaoshengxue Tablet (p<0.05).2.The effect of Kidney-Yang deficiency type was superior to that of Kidney-Yin deficiency type(p<0.05). 3.The expression level of P-ERK1/2 in CAA patients were lower than that in normal group(P<0.05). P-JNK and P-P38 protein levels were higher than that of normal group (P<0.05), and the level of P-ERK1/2 in Kidney-yang deficient patients higher than that of Kidney-yin deficiency (P <0.05), P-JNK lower than the Kidney-yin deficiency (P <0.05), BSSXG can adjusted the abnormal expression of three protein. 4. The mRNA expression of bFGF and bFGFR of CAA lower than that of normal group (P<0.05). After treatment BSSXG made the mRNA expression of bFGF and bFGFR levels increased (P <0.05), and the effect of Kidney-Yin deficiency had a significant difference with Kidney -Yang dificiency (P <0.05).
Conclusion: 1. BSSXG have better clinical efficacy, it is an effective drug for treatment of CAA. 2. The lower expression of P-ERK1/2 and the higher expression of P-JNK and P-P38 in CAA bone marrow stomal may be one of the mechanisms of bone marrow microenvironment environmental adhesion dysfunction. 3.BSSXG can significantly enhance the P-ERK1/2 expression and inhibite stromal cell apoptosis, improve the bone marrow micro-environment for cell proliferation, differentiation and survival returned to normal. Meanwhile, reduction of P-JNK, P-P38 protein levels can improve the hematopoietic stem cell / progenitor cell homing, migration, and enhance the adhesion of hematopoietic signal transduction. 4.P-ERK1/2 expression in the kidney-Yang deficiency was higher than that in patients with Kidney-Yin deficiency, P-JNK in the kidney-Yang type protein level in patients lower than kidney-Yin deficiency. These results may make references for the TCM treatments of CAA. 5.This study suggest that BSSXG can reulate the bFGF and bFGFR expression levels. This can proliferate and directionally differentiate and promote bone marrow angiogenesis, improve the hematopoietic microenvironment. It also can conclude that the mRNA of bFGF and bFGFR of kidney-Yang deficiency can be corrected better than that of in kidney-Yin deficiency.
引文
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