顺铂致卵巢功能早衰发病机制与金雀异黄素调节作用的实验研究
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摘要
一研究背景
近年来,恶性肿瘤的发病率呈持续升高,因化疗而导致卵巢功能低下和不孕的患者日渐增多,成为POF发病的一个重要原因。化疗治疗用药易引发生肝、肾毒性,形成肝肾阴虚证,虚火内扰,冲任失充,气血化源不足,性腺失养而功能低下,甚至造成闭经和不孕。本病确切病因尚不清楚,在临床防治中多采用激素替代治疗(hormone replacement therapy,HRT)方法。但大量报道表明,目前的HRT可增加了雌激素依赖性肿瘤的发病风险。寻找安全、高效物植物药物是目前POF防治研究中的难点之一。
二研究目的
以建立稳定的化疗损伤性POF动物模型为平台,探讨GEN对化疗损伤性POF的治疗作用及机制,揭示中药单体的分子药理作用靶标,挖掘POF发病及GEN治疗作用的基因表达特征,绘制其网络调控的生物信息学图谱,从而完善中药雌激素受体调节剂HRT治疗作用学说。
三研究方法
应用顺铂(cis-diamminedichloroplatinum, CDDP)注射ICR小鼠腹腔给药方法,构建化疗损伤性POF动物模型,为系统化研究POF搭建动物实验平台;采集大鼠卵巢颗粒细胞进行体外原代培养,为深入研究POF建立起细胞研究平台;运用免疫组织化学技术、电子显微镜技术、蛋白免疫印迹技术、酶联免疫技术、流式细胞分析技术、激光共聚焦技术、基因芯片技术和生物信息分析技术等方法,系统研究POF的病理机制及GEN的影响作用途径与作用靶点。
四研究结果
1.化疗损伤性POF动物模型建立与评价
应用3.0mg/kg剂量的CDDP,对ICR小鼠连续腹腔注射给药7d,即可较好地模拟出化疗损伤性卵巢功能早衰的发病过程:其生物学行为性状改变符合POF的临床表现,证属肝肾阴虚;血清卵巢激素水平下降,促性腺素水平升高;卵巢组织学出现生长卵泡发育阻滞,卵泡闭锁增加,间质部分增生、纤维化样改变。通过病理机制分析,发现CDDP是通过两条途径影响卵巢功能:①对DNA直接损伤;②氧化损伤作用。此模型成功率高,成模时间短,动物模型评价效果好。
2.GEN对化疗损伤性POF的治疗作用及机制
GEN可明显改善模型动物生物学状态,体重增加,周期排卵和动情周期恢复近正常;血清雌二醇和孕酮水平恢复近正常,且随GEN剂量增加,而孕酮表现更为明显;雌、孕激素受体免疫组化结果表明,GEN可明显上调节ER和PR表达,以PR增强为著;GEN可降低卵巢组织中丙二醛(MDA)含量,提高其总抗氧化能力(T-AOC);GEN可相对降低MMP-2、MMP-9、TGFβ和LN的表达,从而有利于卵巢组织结构的重建,促进卵泡成熟与排出;GEN用药后卵巢颗粒细胞器丰富,高尔基复合体、滑面内质网较多,卵泡膜内层细胞(间质腺细胞)高尔基复合体、粗面内质网及线粒体较多,核糖体丰富。
GEN可能主要是通过三条作用途径发挥其改善卵巢功能的作用:①较强的抗氧化损伤作用,修复损伤的DNA,从而激活卵巢颗粒内源性蛋白激酶活性,重新构建起激素合成与分泌的分子基础;②增加卵巢细胞ER和PR的表达,提高受体敏感性,并以PR表达增加为主要,从而对卵巢功能起到自我校正作用;③调节细胞外基质的形成与降解的平衡,从而改善卵泡和颗粒细胞功能状态,促进其分化与成熟。
3.GEN对CDDP作用后卵巢颗粒细胞功能调节机制
CDDP可明显抑制卵巢颗粒细胞增殖,其对细胞周期较为明显的作用位点是S期,并可使细胞周期阻滞于G1-M期,凋亡细胞明显增加。GEN可对抗CDDP的损伤效应,提高细胞的分化与增殖能力,明显消除细胞周期阻滞现象,其最佳作用时间点为24h,此作用与GEN呈剂量关系;GEN可提高卵巢颗粒细胞内Ca2+浓度,抑制CDDP造成的凋亡作用。
4.POF发病及GEN影响的差异基因表达谱
基因芯片信息分析表明,CDDP可上调137条基因表达,下调110条基因表达,对卵巢细胞功能表达起到明显的抑制作用,这些基因主要作用于DNA合成、跨膜能量代谢和细胞核因子激活等方面,从而造成部分基因网络调控失衡而致病;GEN可上调22条基因表达,下调38条基因表达,这些基因主要与激素合成、DNA损伤修复和能量代谢密切相关,对于部分细胞信号转导中关键通路的建立与网络化调控起到了重要作用。五研究结论
通过综合运用形态学、分子生物学和生物信息学技术与理论,所建立的动物模型较为全面地表现了POF病理过程。CDDP主要是通过氧化损伤和影响DNA合成完成的。GEN是较为理想的POF治疗药物,主要是通过改善卵巢细胞周期,抑制卵巢颗粒细胞凋亡,激活ER和PR活力,改善卵巢间质功能状态,为卵巢重构和排卵奠定基础。
Background
Premature ovarian failure (POF) is a common endocrine illness of Gynecology clinically, which is characterized by cession of menstruation before or at the age of 40 with elevated gonadotrophins and low estrogen levels. In recent years, the incidence of carcinoma has an increasing tendency, and there are more and more patients suffering from ovarian deficiency and infertility caused by chemotherapy which becomes one of the important etiological factors of POF. It is reported that nephrotoxicity and hepatotoxicity are commonly encountered when undertaking chemotherapy, which induce liver-kidney yin deficiency, and then deficiency fire disturbs, which lead to disorder of Chong and Ren Meridians. Subsequently, deficiency of resource of Qi and blood will occurred. The gonad fails to get enough nourishment, which brings about ovarian deficiency. What’s more, it may lead to amenorrhea and infertility. The specific etiological factor is not clear yet. Hormone replacement therapy(HRT) is used to prevent and treat this disease clinically. However, according to a large amount of reports, HRT can increase the risk of suffering from estrogen-independed tumor. It is one of the difficult problems of the prevention and treatment of POF to look for safe and effective herb medicines. Objective
On the base of establishing the animal model of chemotherapy damaged POF, by exploring the therapeutic effect of genistein on POF and its mechanism, and revealing the target point of molecular pharmacology of herb monomer, finding the character of gene expression in pathogenic mechanism of POF and therapeutic effect of genistein, and then drawing the bioinformatics profile of its net regulation, Chinese medical estrogen receptor regulator theory will be completed. Method
The animal model of POF induced by chemotherapy damage is established by using ICR mice injected i.p. with CDDP. The animal experiment is provided to research POF systematically. Primary culture of granulosa cell from the ovaries of rats is provided the cellular research method to further research of POF. By using the techniques of immunohistochemistry, electronmicroscope, protein immunoblotting, flow cytometry, gene chip and analysis of bioinformatics , pathomechanism of POF and the effective pathway and the target point of GEN are researched systematically.
Result
1. The establishment of the animal model of chemotherapy damaged POF and its evaluation
ICR mice were i.p. injected daily with cisplatin at doses of 3.0mg/kg body weight daily for 7days.This method can imitate the pathogenetic progress of POF induced by the chemotherapy damaged. The biological behavior character change of the mice is consonant with the clinical manifestation of POF, and its syndrome belongs to liver and kidney yin deficiency. Serum levels of ovarian hormones are decreased and serum levels of gonadotrophins are increased. Histology of the ovary shows that development of preantral follicle stopped, with the number of atretic follicle increased and local hyperplasia of stroma which have change of fribrosis. CDDP damages ovarian function by two following ways:①damaging DNA directly;②oxidative damage. This model has high achievement ratio, short time of establishment and good result of evaluation.
2. The effect of GEN on chemotherapy damaged POF and its mechanism
GEN can improve the biological situation of the animal obviously with increasing weight, intermittent ovulation and estrous cycle’s restoring to nearly normal situation. Serum levels of estrogen and progesterone restore to nearly normal levels. With the increasing dose of GEN, the change of progesterone is obvious. The result of immunohistochemistry of estrogen receptor (ER) and progesterone receptor (PR) shows that GEN can up-regulate the expression of ER and PR, and the expression of PR is increased more markedly. GEN can reduce the content of MDA in the ovary, and elevate ovarian total antioxidative capacity (T-AOC). Also, GEN can down-regulate the expression the MMP-2, MMP-9, TGF-βand LH correspondingly, which are good for reconstruction of ovarian structure and maturation of follicles and ovulation. After GEN is taken, cellular organs of granulosa cells are rich. Golgi complexes and smooth endoplasmic reticulum become more. There are more Golgi complexes, rough endoplasmic reticulums and mitochondria in interstitial gland cells. Ribosome is also rich in interstitial gland cells.
GEN may improve ovarian function by three following ways:①having stronge anti-oxidative damage, restoring damaged DNA , activating the activity of the endogenous protease in granulose cells and then reconstructing the molecular base of synthesis and secretion of hormone②increasing the expression of ER and PR, raising the sensitivity of the receptor, and then achieving self correction are exerted to ovarian function characterized by increased expression of PR③regulating the balance between the formation and degradation of the extracellular matrix, improving the function situation of the granulosa cells and follicles, and promoting differentiation and maturation of the follicles.
3. Regulating mechanism of GEN to the function of CDDP affected granulosa cells of ovary.
CDDP can inhibit the proliferation of granulosa cells of ovary. Its effecting stage to the cell cycle is S stage, and it can arrest cell cycle to the G1-M stage. In this stage, the number of apoptotic cell increased evidently. GEN is against damaging effect of CDDP, and it can improve the differentiation and proliferation of the cells to make the blockage of the cell cycle disappear. This effect is related to the dose of GEN. The best time of affecting is 24 hour. GEN will rise the amount of Ca2+ in granulosa cells and inhibit the death of them.
4. Differential gene expression profile of pathogenic progress of POF and therapeutic effects of genistein
Analysis of Gene chip shows that CDDP can up-regulate 137 genes expression, and down-regulate 110 genes expression, which are related with synthesis of DNA, energy metabolism crossing membrane, activation of cellular nuclear factor. CDDP also has an inhibiting effect on functional expression of ovarian cells, and then result in imbalance of net regulation of some genes. GEN can up-regulate expression of 22 genes and down-regulate expression of 38 genes, which are closely related with synthesis of hormone ,repair of damaged DNA and energy metabolism. GEN puts an important effect on establishment of key pathway of cellular signal conduction partly and net regulation.
Conclusion
Using the theory and technique of morphology, molecular biology and bioinformatics, pathologic processes of POF are displayed systematically by establishing this animal model. CDDP mainly affects the ovarian function by inhibiting the synthesis of DNA and oxidative damage. GEN can improve cell cycle and activate ER and PR, ameliorate the ovary function, and inhibit the death of granulaosa cells, which are the basis for ovarian reconstruction and ovulation. Therefor, GEN is an ideal medicine for treating POF.
近年来,恶性肿瘤的发病率呈持续升高,因化疗而导致卵巢功能低下和不孕的患者日渐增多,成为POF发病的一个重要原因。化疗治疗用药易引发生肝、肾毒性,形成肝肾阴虚证,虚火内扰,冲任失充,气血化源不足,性腺失养而功能低下,甚至造成闭经和不孕。本病确切病因尚不清楚,在临床防治中多采用激素替代治疗(hormone replacement therapy,HRT)方法。但大量报道表明,目前的HRT可增加了雌激素依赖性肿瘤的发病风险。寻找安全、高效物植物药物是目前POF防治研究中的难点之一。
二研究目的
以建立稳定的化疗损伤性POF动物模型为平台,探讨GEN对化疗损伤性POF的治疗作用及机制,揭示中药单体的分子药理作用靶标,挖掘POF发病及GEN治疗作用的基因表达特征,绘制其网络调控的生物信息学图谱,从而完善中药雌激素受体调节剂HRT治疗作用学说。
三研究方法
应用顺铂(cis-diamminedichloroplatinum, CDDP)注射ICR小鼠腹腔给药方法,构建化疗损伤性POF动物模型,为系统化研究POF搭建动物实验平台;采集大鼠卵巢颗粒细胞进行体外原代培养,为深入研究POF建立起细胞研究平台;运用免疫组织化学技术、电子显微镜技术、蛋白免疫印迹技术、酶联免疫技术、流式细胞分析技术、激光共聚焦技术、基因芯片技术和生物信息分析技术等方法,系统研究POF的病理机制及GEN的影响作用途径与作用靶点。
四研究结果
1.化疗损伤性POF动物模型建立与评价
应用3.0mg/kg剂量的CDDP,对ICR小鼠连续腹腔注射给药7d,即可较好地模拟出化疗损伤性卵巢功能早衰的发病过程:其生物学行为性状改变符合POF的临床表现,证属肝肾阴虚;血清卵巢激素水平下降,促性腺素水平升高;卵巢组织学出现生长卵泡发育阻滞,卵泡闭锁增加,间质部分增生、纤维化样改变。通过病理机制分析,发现CDDP是通过两条途径影响卵巢功能:①对DNA直接损伤;②氧化损伤作用。此模型成功率高,成模时间短,动物模型评价效果好。
2.GEN对化疗损伤性POF的治疗作用及机制
GEN可明显改善模型动物生物学状态,体重增加,周期排卵和动情周期恢复近正常;血清雌二醇和孕酮水平恢复近正常,且随GEN剂量增加,而孕酮表现更为明显;雌、孕激素受体免疫组化结果表明,GEN可明显上调节ER和PR表达,以PR增强为著;GEN可降低卵巢组织中丙二醛(MDA)含量,提高其总抗氧化能力(T-AOC);GEN可相对降低MMP-2、MMP-9、TGFβ和LN的表达,从而有利于卵巢组织结构的重建,促进卵泡成熟与排出;GEN用药后卵巢颗粒细胞器丰富,高尔基复合体、滑面内质网较多,卵泡膜内层细胞(间质腺细胞)高尔基复合体、粗面内质网及线粒体较多,核糖体丰富。
GEN可能主要是通过三条作用途径发挥其改善卵巢功能的作用:①较强的抗氧化损伤作用,修复损伤的DNA,从而激活卵巢颗粒内源性蛋白激酶活性,重新构建起激素合成与分泌的分子基础;②增加卵巢细胞ER和PR的表达,提高受体敏感性,并以PR表达增加为主要,从而对卵巢功能起到自我校正作用;③调节细胞外基质的形成与降解的平衡,从而改善卵泡和颗粒细胞功能状态,促进其分化与成熟。
3.GEN对CDDP作用后卵巢颗粒细胞功能调节机制
CDDP可明显抑制卵巢颗粒细胞增殖,其对细胞周期较为明显的作用位点是S期,并可使细胞周期阻滞于G1-M期,凋亡细胞明显增加。GEN可对抗CDDP的损伤效应,提高细胞的分化与增殖能力,明显消除细胞周期阻滞现象,其最佳作用时间点为24h,此作用与GEN呈剂量关系;GEN可提高卵巢颗粒细胞内Ca2+浓度,抑制CDDP造成的凋亡作用。
4.POF发病及GEN影响的差异基因表达谱
基因芯片信息分析表明,CDDP可上调137条基因表达,下调110条基因表达,对卵巢细胞功能表达起到明显的抑制作用,这些基因主要作用于DNA合成、跨膜能量代谢和细胞核因子激活等方面,从而造成部分基因网络调控失衡而致病;GEN可上调22条基因表达,下调38条基因表达,这些基因主要与激素合成、DNA损伤修复和能量代谢密切相关,对于部分细胞信号转导中关键通路的建立与网络化调控起到了重要作用。五研究结论
通过综合运用形态学、分子生物学和生物信息学技术与理论,所建立的动物模型较为全面地表现了POF病理过程。CDDP主要是通过氧化损伤和影响DNA合成完成的。GEN是较为理想的POF治疗药物,主要是通过改善卵巢细胞周期,抑制卵巢颗粒细胞凋亡,激活ER和PR活力,改善卵巢间质功能状态,为卵巢重构和排卵奠定基础。
Background
Premature ovarian failure (POF) is a common endocrine illness of Gynecology clinically, which is characterized by cession of menstruation before or at the age of 40 with elevated gonadotrophins and low estrogen levels. In recent years, the incidence of carcinoma has an increasing tendency, and there are more and more patients suffering from ovarian deficiency and infertility caused by chemotherapy which becomes one of the important etiological factors of POF. It is reported that nephrotoxicity and hepatotoxicity are commonly encountered when undertaking chemotherapy, which induce liver-kidney yin deficiency, and then deficiency fire disturbs, which lead to disorder of Chong and Ren Meridians. Subsequently, deficiency of resource of Qi and blood will occurred. The gonad fails to get enough nourishment, which brings about ovarian deficiency. What’s more, it may lead to amenorrhea and infertility. The specific etiological factor is not clear yet. Hormone replacement therapy(HRT) is used to prevent and treat this disease clinically. However, according to a large amount of reports, HRT can increase the risk of suffering from estrogen-independed tumor. It is one of the difficult problems of the prevention and treatment of POF to look for safe and effective herb medicines. Objective
On the base of establishing the animal model of chemotherapy damaged POF, by exploring the therapeutic effect of genistein on POF and its mechanism, and revealing the target point of molecular pharmacology of herb monomer, finding the character of gene expression in pathogenic mechanism of POF and therapeutic effect of genistein, and then drawing the bioinformatics profile of its net regulation, Chinese medical estrogen receptor regulator theory will be completed. Method
The animal model of POF induced by chemotherapy damage is established by using ICR mice injected i.p. with CDDP. The animal experiment is provided to research POF systematically. Primary culture of granulosa cell from the ovaries of rats is provided the cellular research method to further research of POF. By using the techniques of immunohistochemistry, electronmicroscope, protein immunoblotting, flow cytometry, gene chip and analysis of bioinformatics , pathomechanism of POF and the effective pathway and the target point of GEN are researched systematically.
Result
1. The establishment of the animal model of chemotherapy damaged POF and its evaluation
ICR mice were i.p. injected daily with cisplatin at doses of 3.0mg/kg body weight daily for 7days.This method can imitate the pathogenetic progress of POF induced by the chemotherapy damaged. The biological behavior character change of the mice is consonant with the clinical manifestation of POF, and its syndrome belongs to liver and kidney yin deficiency. Serum levels of ovarian hormones are decreased and serum levels of gonadotrophins are increased. Histology of the ovary shows that development of preantral follicle stopped, with the number of atretic follicle increased and local hyperplasia of stroma which have change of fribrosis. CDDP damages ovarian function by two following ways:①damaging DNA directly;②oxidative damage. This model has high achievement ratio, short time of establishment and good result of evaluation.
2. The effect of GEN on chemotherapy damaged POF and its mechanism
GEN can improve the biological situation of the animal obviously with increasing weight, intermittent ovulation and estrous cycle’s restoring to nearly normal situation. Serum levels of estrogen and progesterone restore to nearly normal levels. With the increasing dose of GEN, the change of progesterone is obvious. The result of immunohistochemistry of estrogen receptor (ER) and progesterone receptor (PR) shows that GEN can up-regulate the expression of ER and PR, and the expression of PR is increased more markedly. GEN can reduce the content of MDA in the ovary, and elevate ovarian total antioxidative capacity (T-AOC). Also, GEN can down-regulate the expression the MMP-2, MMP-9, TGF-βand LH correspondingly, which are good for reconstruction of ovarian structure and maturation of follicles and ovulation. After GEN is taken, cellular organs of granulosa cells are rich. Golgi complexes and smooth endoplasmic reticulum become more. There are more Golgi complexes, rough endoplasmic reticulums and mitochondria in interstitial gland cells. Ribosome is also rich in interstitial gland cells.
GEN may improve ovarian function by three following ways:①having stronge anti-oxidative damage, restoring damaged DNA , activating the activity of the endogenous protease in granulose cells and then reconstructing the molecular base of synthesis and secretion of hormone②increasing the expression of ER and PR, raising the sensitivity of the receptor, and then achieving self correction are exerted to ovarian function characterized by increased expression of PR③regulating the balance between the formation and degradation of the extracellular matrix, improving the function situation of the granulosa cells and follicles, and promoting differentiation and maturation of the follicles.
3. Regulating mechanism of GEN to the function of CDDP affected granulosa cells of ovary.
CDDP can inhibit the proliferation of granulosa cells of ovary. Its effecting stage to the cell cycle is S stage, and it can arrest cell cycle to the G1-M stage. In this stage, the number of apoptotic cell increased evidently. GEN is against damaging effect of CDDP, and it can improve the differentiation and proliferation of the cells to make the blockage of the cell cycle disappear. This effect is related to the dose of GEN. The best time of affecting is 24 hour. GEN will rise the amount of Ca2+ in granulosa cells and inhibit the death of them.
4. Differential gene expression profile of pathogenic progress of POF and therapeutic effects of genistein
Analysis of Gene chip shows that CDDP can up-regulate 137 genes expression, and down-regulate 110 genes expression, which are related with synthesis of DNA, energy metabolism crossing membrane, activation of cellular nuclear factor. CDDP also has an inhibiting effect on functional expression of ovarian cells, and then result in imbalance of net regulation of some genes. GEN can up-regulate expression of 22 genes and down-regulate expression of 38 genes, which are closely related with synthesis of hormone ,repair of damaged DNA and energy metabolism. GEN puts an important effect on establishment of key pathway of cellular signal conduction partly and net regulation.
Conclusion
Using the theory and technique of morphology, molecular biology and bioinformatics, pathologic processes of POF are displayed systematically by establishing this animal model. CDDP mainly affects the ovarian function by inhibiting the synthesis of DNA and oxidative damage. GEN can improve cell cycle and activate ER and PR, ameliorate the ovary function, and inhibit the death of granulaosa cells, which are the basis for ovarian reconstruction and ovulation. Therefor, GEN is an ideal medicine for treating POF.
引文
[1] Blumenfeld Z, Shapiro D, Shteinberg M, et al. Preservation of fertility and ovarian function and minimizing gonadotoxicity in young women with systemic lupus erythematosus treated by chemotherapy. Lupus. 2000, 9(6): 401-405
[2] Huong du L, Amoura Z, Duhaut P, et al. Risk of ovarian failure and fertility after intravenous cyclophosphamide. A study in 84 patients. J Rheumatol. 2002, 29(12): 2571-2576
[3] De Maio E, Gravina A, Pacilio C, et al. Compliance and toxicity of adjuvant CMF in elderly breast cancer patients: a single-center experience.BMC Cancer. 2005, 5(1):30-35
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