“劳倦过度、房室不节”致肾阳虚及补肾阳对小鼠甲状腺轴及睾丸基因表达谱的影响
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摘要
目的：探讨“劳倦过度、房室不节”致肾阳虚小鼠下丘脑-垂体-甲状腺轴的神经内分泌、病理形态学、凋亡相关基因表达的变化,以及下丘脑-垂体-性腺轴的睾丸基因表达谱的改变,同时,研究金匮肾气丸对肾阳虚小鼠甲状腺轴及性腺轴影响的部分作用机理。
方法：建立“劳倦过度、房室不节”肾阳虚小鼠模型。采用光镜、电镜、放射免疫分析、免疫组织化学分析、基因芯片技术等方法,对正常、肾阳虚、补肾阳三种小鼠进行甲状腺的组织形态学及超微结构观察、血清甲状腺轴激素TSH、T3、T4含量测定、甲状腺组织凋亡相关基因Fas、FasL、Bcl-2、Bax和Caspase-3表达检测,并绘制睾丸组织基因表达谱比较的散点图,对睾丸组织基因芯片差异表达基因进行筛选和分析。
结果：
1.通过对小鼠体温、体重及一般状况的观察,表明“劳倦过度、房室不节”肾阳虚小鼠模型复制成功；
2.肾阳虚小鼠存在甲状腺病理形态学的损伤,金匮肾气丸可以改善肾阳虚小鼠甲状腺组织形态及超微结构发生的损伤；
3.肾阳虚小鼠存在甲状腺轴激素水平下降,金匮肾气丸治疗后可上调肾阳虚小鼠血清甲状腺轴激素水平；
4.肾阳虚小鼠可能存在甲状腺组织促凋亡基因Bax表达增加,金匮肾气丸可使肾阳虚小鼠甲状腺组织FasL、Bax蛋白表达明显下降；
5.绘制了模型组/对照组、治疗组/模型组基因表达谱比较的散点图,筛选出差异表达基因,模型组/对照组上调2425个,下调3080个,治疗组/模型组上调99个,下调96个。模型组/对照组上调而治疗组/模型组下调的基因10个,模型组/对照组下调而治疗组/模型组上调的基因15个,均主要与细胞结构/功能、物质/能量代谢、信号转导/传递、转录/翻译、增殖/分化、细胞周期、细胞凋亡等有关。并探讨了金匮肾气丸使模型组小鼠下调的睾丸基因Usp39、Jam2、Cdc20上调、上调的睾丸基因Argl、Akap10下调的作用机制。
结论：“劳倦过度、房室不节”肾阳虚小鼠甲状腺轴激素含量下降,甲状腺组织形态及超微结构损伤,甲状腺促凋亡基因Bax表达增加,睾丸组织中与细胞周期、能量代谢及精子发生相关的基因表达谱改变,导致小鼠甲状腺轴及性腺轴功能低下。金匱肾气丸可以提高肾阳虚小鼠甲状腺轴激素含量,改善甲状腺的组织形态及超微结构,并可通过降低FasL、Bax的表达水平,抑制甲状腺细胞凋亡,促进甲状腺轴功能恢复,还可以调节与细胞周期及精子发生等相关睾丸基因的表达,促进性腺轴功能恢复。
Objective:This experimental study focused on variations of neuroendocrine, pathological morphology, apoptosis-related proteins of hypothalamic-pituitary-thyroid-axis and changes of testis gene profile of hypothalamic-pituitary-gonad-axis in kidney-yang deficiency syndrome mice model induced by overfatigue and sexual overstrain. Mealwhile, the effects of Jinguishenqi bolus on thyroid-axis and gonad-axis were explored in kidney-yang deficiency syndrome mice model.
Methods:The mice model of kidney-yang deficiency syndrome induced by overfatigue and sexual overstrain were established. Observe the morphological changes and ultrastructural variation of thyroid with light microscope and electron microscopy, detect the content of thyroid axis hormone in serum such as TSH, T3 and T4 by radioimmunoassay, determine the expression of Fas, FasL, Bcl-2, Bax and Caspase-3 in mice thyroid by immunohistochemical method among control group, kidney-yang deficiency syndrome group and treatment group. In addition, two scatter plots of gene expression profile were drawn and differentially expressed genes were detected and screened.
Results:
1. Mice model of kidney-yang deficiency syndrome induced by overfatigue and sexual overstrain were established successfully by observing the changes of mice temperature, weight and general condition.
2. Pathmorphological injuries of thyroid glands were observed in mice with kidney-yang deficiency. Jinguishenqi bolus had certain modulation of morphological and ultrastructural variation.
3. There had been a decrease of hormone level of thyroid axis in serum in mice model of kidney-yang deficiency syndrome, but with kidney-yang nourishing therapy the serum hormone level increased.
4. Expression of apoptosis related gene Bax in mice model group were higher than that in mice control group, but expression of Bax and FasL in treatment group mice lower than those in mice model group.
5. Two scatter plots of gene expression profile were drawn with model/control group and treatment/model group. Differentially expressed genes were screened, including 2425 up-regulated genes and 3080 down-regulated genes in model/control group,99 up-regulated genes and 96 down-regulated genes in treatment/model group. There were ten genes among up-regulated genes in model/control group but down-regulated in treatment/model group, and fifteen genes among down-regulated genes in model/control group but up-regulated in treatment/model group. These genes were mainly related to cellular structure/function, material/energy metabolism, signal transduction/relay, transcription/translation, proliferation/differentiation, cell cycle and cell apoptosis. Abnormal expression of testis genes such as Usp39, Jam2, Cdc20, Arg1 and Akap10 in model/control group was modulated in treatment/model group by Jinguishenqi bolus.
Conclusion:The results indicate that overfatigue and sexual overstrain could lower the hormone level of thyroid axis, promote cell apoptosis of thyroid by high expression of apoptosis related gene Bax and change the level of testis genes expression related to cell cycle, energy metabolism and spermatogenesis. Jinguishenqi bolus could inhibit cell apoptosis by decreasing the level of Bax and FasL to promote thyroid axis function and modulate the level of testis genes expression related to cell cycle and spermatogenesis to promote gonad axis function.
方法：建立“劳倦过度、房室不节”肾阳虚小鼠模型。采用光镜、电镜、放射免疫分析、免疫组织化学分析、基因芯片技术等方法,对正常、肾阳虚、补肾阳三种小鼠进行甲状腺的组织形态学及超微结构观察、血清甲状腺轴激素TSH、T3、T4含量测定、甲状腺组织凋亡相关基因Fas、FasL、Bcl-2、Bax和Caspase-3表达检测,并绘制睾丸组织基因表达谱比较的散点图,对睾丸组织基因芯片差异表达基因进行筛选和分析。
结果：
1.通过对小鼠体温、体重及一般状况的观察,表明“劳倦过度、房室不节”肾阳虚小鼠模型复制成功；
2.肾阳虚小鼠存在甲状腺病理形态学的损伤,金匮肾气丸可以改善肾阳虚小鼠甲状腺组织形态及超微结构发生的损伤；
3.肾阳虚小鼠存在甲状腺轴激素水平下降,金匮肾气丸治疗后可上调肾阳虚小鼠血清甲状腺轴激素水平；
4.肾阳虚小鼠可能存在甲状腺组织促凋亡基因Bax表达增加,金匮肾气丸可使肾阳虚小鼠甲状腺组织FasL、Bax蛋白表达明显下降；
5.绘制了模型组/对照组、治疗组/模型组基因表达谱比较的散点图,筛选出差异表达基因,模型组/对照组上调2425个,下调3080个,治疗组/模型组上调99个,下调96个。模型组/对照组上调而治疗组/模型组下调的基因10个,模型组/对照组下调而治疗组/模型组上调的基因15个,均主要与细胞结构/功能、物质/能量代谢、信号转导/传递、转录/翻译、增殖/分化、细胞周期、细胞凋亡等有关。并探讨了金匮肾气丸使模型组小鼠下调的睾丸基因Usp39、Jam2、Cdc20上调、上调的睾丸基因Argl、Akap10下调的作用机制。
结论：“劳倦过度、房室不节”肾阳虚小鼠甲状腺轴激素含量下降,甲状腺组织形态及超微结构损伤,甲状腺促凋亡基因Bax表达增加,睾丸组织中与细胞周期、能量代谢及精子发生相关的基因表达谱改变,导致小鼠甲状腺轴及性腺轴功能低下。金匱肾气丸可以提高肾阳虚小鼠甲状腺轴激素含量,改善甲状腺的组织形态及超微结构,并可通过降低FasL、Bax的表达水平,抑制甲状腺细胞凋亡,促进甲状腺轴功能恢复,还可以调节与细胞周期及精子发生等相关睾丸基因的表达,促进性腺轴功能恢复。
Objective:This experimental study focused on variations of neuroendocrine, pathological morphology, apoptosis-related proteins of hypothalamic-pituitary-thyroid-axis and changes of testis gene profile of hypothalamic-pituitary-gonad-axis in kidney-yang deficiency syndrome mice model induced by overfatigue and sexual overstrain. Mealwhile, the effects of Jinguishenqi bolus on thyroid-axis and gonad-axis were explored in kidney-yang deficiency syndrome mice model.
Methods:The mice model of kidney-yang deficiency syndrome induced by overfatigue and sexual overstrain were established. Observe the morphological changes and ultrastructural variation of thyroid with light microscope and electron microscopy, detect the content of thyroid axis hormone in serum such as TSH, T3 and T4 by radioimmunoassay, determine the expression of Fas, FasL, Bcl-2, Bax and Caspase-3 in mice thyroid by immunohistochemical method among control group, kidney-yang deficiency syndrome group and treatment group. In addition, two scatter plots of gene expression profile were drawn and differentially expressed genes were detected and screened.
Results:
1. Mice model of kidney-yang deficiency syndrome induced by overfatigue and sexual overstrain were established successfully by observing the changes of mice temperature, weight and general condition.
2. Pathmorphological injuries of thyroid glands were observed in mice with kidney-yang deficiency. Jinguishenqi bolus had certain modulation of morphological and ultrastructural variation.
3. There had been a decrease of hormone level of thyroid axis in serum in mice model of kidney-yang deficiency syndrome, but with kidney-yang nourishing therapy the serum hormone level increased.
4. Expression of apoptosis related gene Bax in mice model group were higher than that in mice control group, but expression of Bax and FasL in treatment group mice lower than those in mice model group.
5. Two scatter plots of gene expression profile were drawn with model/control group and treatment/model group. Differentially expressed genes were screened, including 2425 up-regulated genes and 3080 down-regulated genes in model/control group,99 up-regulated genes and 96 down-regulated genes in treatment/model group. There were ten genes among up-regulated genes in model/control group but down-regulated in treatment/model group, and fifteen genes among down-regulated genes in model/control group but up-regulated in treatment/model group. These genes were mainly related to cellular structure/function, material/energy metabolism, signal transduction/relay, transcription/translation, proliferation/differentiation, cell cycle and cell apoptosis. Abnormal expression of testis genes such as Usp39, Jam2, Cdc20, Arg1 and Akap10 in model/control group was modulated in treatment/model group by Jinguishenqi bolus.
Conclusion:The results indicate that overfatigue and sexual overstrain could lower the hormone level of thyroid axis, promote cell apoptosis of thyroid by high expression of apoptosis related gene Bax and change the level of testis genes expression related to cell cycle, energy metabolism and spermatogenesis. Jinguishenqi bolus could inhibit cell apoptosis by decreasing the level of Bax and FasL to promote thyroid axis function and modulate the level of testis genes expression related to cell cycle and spermatogenesis to promote gonad axis function.
引文
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