绝经后女性重度血管性痴呆患者雌激素治疗效果与外周血单个核细胞ERR亚型表达关系的研究
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摘要
目的:探讨雌激素受体相关受体ERR (estrogen receptor related receptors,ERR)α、β、γ在VD患者外周血单个核细胞表达水平与雌激素疗效之间的关系。
方法:以雌激素治疗的80例绝经后重度VD患者(有效组40例,无效组40例)在施行雌激素治疗前后的血液样本作为研究对象,同年龄阶段的80例正常老年绝经女性被用来作为对照研究。VD采用简易精神状态检查(MMSE-R)和临床痴呆分级表的判定。用ELISA测定各组患者治疗前后的血清雌二醇浓度并分析其与相关并发症之间的关系,正常绝经后妇女的血清雌二醇浓度被用来做对照。采用半定量RT-PCR方法检测VD有效组和无效组患者ERRs家族各亚型的mRNA在雌激素治疗前后的表达,正常对照组的各亚型的表达用来对照;采用Western Blot印迹的方法检测ERRs各亚型蛋白在雌激素治疗前后的表达。
结果:
1.老年女性血管性痴呆患者血清雌二醇水平显著低于年龄、性别匹配的正常人群,雌激素替代疗法能使血清雌二醇水平升高。
2.血管性痴呆患者血清雌二醇水平和患者是否同时患糖尿病有关,治疗前后的糖尿病患者血清雌二醇水平显著低于无糖尿病者。
3.RT-PCR分析及Western Blot免疫印迹显示:ERRα、β和γ的mRNA和蛋白在VD患者显示特殊的表达模式:ERRα在无效组低表达、在有效组高表达,但表达均低于正常对照;ERRβ在有效组、无效组和正常对照之间基本无变化;ERRγ在无效组高表达、在有效组低表达、正常对照表达最低。
4.临床治疗重度VD患者可通过检测外周血单个核细胞的ERRα/ERRγmRNA或蛋白表达的比值推测治疗效果,或者作为雌激素治疗重度VD患者的适应症。
结论:与正常对照相比,血管性痴呆患者外周血单个核细胞ERRα表达较低、ERRγ表达较高。经雌激素治疗有效患者,ERRα表达显著升高, ERRγ表达显著下降。本研究提示ERRα/ ERRγ比值的改变可能与血管性痴呆的发病、雌激素的疗效有密切的关系,此比值或可成为临床上雌激素治疗重度VD患者的参考指标。EERs将是雌激素治疗重度血管性痴呆的分子生物学基础。
Objective: To explore the relationship between estrogen receptor-related receptor (ERR)α,β,γexpressions in peripheral blood mononuclear cells and estrogen therapeutic effect in severe VD patients.
Methods: Take 40 patients with severe VD who were effective to estrogen therapy as the test group, and another 40 patients with severe VD who failed to estrogen therapy as the control group. Reverse transcription polymerase chain reaction was used to detect the mRNA of various subtypes of ERR family and western blot was applied to determine the protein expression of ERR. We diagnosed the severe VD with Mini-mental state examination (MMSE-R) and clinical dementia rating table.
Results:
1. Serum estradiol level was significantly lower in elderly women patients of vascular dementia than healthy controls with correspondencing age and gender, and estrogen replacement therapy could increase serum estradiol levels.
2. Serum estradiol levels in vascular dementia patient were associated with diabetes, and were markedly higher in patients with diabetes than those in patients without diabetes before and after estrogen treatment.
3. RT-PCR and Western Blot analysis showed: there was a unique expression pattern in the mRNA and protein expressions of ERRα,βandγin the VD patients. ERRαmRNA and protein expression was lower in the ineffective group and higher in the effective group, but the levels of ERRαmRNA and protein both in ineffective group and effective group were lower that those in the healthy control group. ERRβshowed no significant differences among the effective group, ineffective group and healthy control. ERRγexpression was higher in ineffective group and lower in the effective group and was the lowest expression in healthy control.
Conclusion: Compared with normal controls, the postmenopausal vascular dementia patients shows lower ERRαexpression and higher ERRγexpression in peripheral blood mononuclear cells. Among effective estrogen treatment patients, ERRαexpression is significantly increased, in contrast, ERRγexpression is dramatically decreased. These findings suggest that the change of ERRα/ERRγratio may be related to the development of vascular dementia and the efficacy of estrogen therapy in severe VD patients and it might be an indication for estrogen therapy. EERs will be the bio-molecular basis of the estrogen treatment in severe vascular dementia.
方法:以雌激素治疗的80例绝经后重度VD患者(有效组40例,无效组40例)在施行雌激素治疗前后的血液样本作为研究对象,同年龄阶段的80例正常老年绝经女性被用来作为对照研究。VD采用简易精神状态检查(MMSE-R)和临床痴呆分级表的判定。用ELISA测定各组患者治疗前后的血清雌二醇浓度并分析其与相关并发症之间的关系,正常绝经后妇女的血清雌二醇浓度被用来做对照。采用半定量RT-PCR方法检测VD有效组和无效组患者ERRs家族各亚型的mRNA在雌激素治疗前后的表达,正常对照组的各亚型的表达用来对照;采用Western Blot印迹的方法检测ERRs各亚型蛋白在雌激素治疗前后的表达。
结果:
1.老年女性血管性痴呆患者血清雌二醇水平显著低于年龄、性别匹配的正常人群,雌激素替代疗法能使血清雌二醇水平升高。
2.血管性痴呆患者血清雌二醇水平和患者是否同时患糖尿病有关,治疗前后的糖尿病患者血清雌二醇水平显著低于无糖尿病者。
3.RT-PCR分析及Western Blot免疫印迹显示:ERRα、β和γ的mRNA和蛋白在VD患者显示特殊的表达模式:ERRα在无效组低表达、在有效组高表达,但表达均低于正常对照;ERRβ在有效组、无效组和正常对照之间基本无变化;ERRγ在无效组高表达、在有效组低表达、正常对照表达最低。
4.临床治疗重度VD患者可通过检测外周血单个核细胞的ERRα/ERRγmRNA或蛋白表达的比值推测治疗效果,或者作为雌激素治疗重度VD患者的适应症。
结论:与正常对照相比,血管性痴呆患者外周血单个核细胞ERRα表达较低、ERRγ表达较高。经雌激素治疗有效患者,ERRα表达显著升高, ERRγ表达显著下降。本研究提示ERRα/ ERRγ比值的改变可能与血管性痴呆的发病、雌激素的疗效有密切的关系,此比值或可成为临床上雌激素治疗重度VD患者的参考指标。EERs将是雌激素治疗重度血管性痴呆的分子生物学基础。
Objective: To explore the relationship between estrogen receptor-related receptor (ERR)α,β,γexpressions in peripheral blood mononuclear cells and estrogen therapeutic effect in severe VD patients.
Methods: Take 40 patients with severe VD who were effective to estrogen therapy as the test group, and another 40 patients with severe VD who failed to estrogen therapy as the control group. Reverse transcription polymerase chain reaction was used to detect the mRNA of various subtypes of ERR family and western blot was applied to determine the protein expression of ERR. We diagnosed the severe VD with Mini-mental state examination (MMSE-R) and clinical dementia rating table.
Results:
1. Serum estradiol level was significantly lower in elderly women patients of vascular dementia than healthy controls with correspondencing age and gender, and estrogen replacement therapy could increase serum estradiol levels.
2. Serum estradiol levels in vascular dementia patient were associated with diabetes, and were markedly higher in patients with diabetes than those in patients without diabetes before and after estrogen treatment.
3. RT-PCR and Western Blot analysis showed: there was a unique expression pattern in the mRNA and protein expressions of ERRα,βandγin the VD patients. ERRαmRNA and protein expression was lower in the ineffective group and higher in the effective group, but the levels of ERRαmRNA and protein both in ineffective group and effective group were lower that those in the healthy control group. ERRβshowed no significant differences among the effective group, ineffective group and healthy control. ERRγexpression was higher in ineffective group and lower in the effective group and was the lowest expression in healthy control.
Conclusion: Compared with normal controls, the postmenopausal vascular dementia patients shows lower ERRαexpression and higher ERRγexpression in peripheral blood mononuclear cells. Among effective estrogen treatment patients, ERRαexpression is significantly increased, in contrast, ERRγexpression is dramatically decreased. These findings suggest that the change of ERRα/ERRγratio may be related to the development of vascular dementia and the efficacy of estrogen therapy in severe VD patients and it might be an indication for estrogen therapy. EERs will be the bio-molecular basis of the estrogen treatment in severe vascular dementia.
引文
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