附子对虚寒证、知母对虚热证大鼠肝全基因表达谱的影响
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摘要
目的:采用中药复方建立虚寒证与虚热证的动物模型,并采用偏最小二乘回归法(PLS)对模型进行评价,探讨符合中医理论的虚寒证和虚热证动物模型的表征评价体系。应用基因芯片技术检测虚寒、虚热证模型大鼠肝全基因表达谱的改变,以及经典寒热中药对虚寒、虚热证模型大鼠肝基因表达的影响,初步研究中药寒、热药性的物质基础及其性效发生机制。
方法:采用中药复方复制动物模型,虚寒组用生石膏、龙胆草、黄柏和知母水煎液,虚热组用熟附子、肉桂、干姜水煎液,连续灌胃14天。模型复制结束后采用PLS法对模型进行评价。虚寒组分为虚寒治疗组与虚寒模型组,其中虚寒治疗组灌胃附子水煎液,虚热组分为虚热治疗组与虚热模型组,其中虚热治疗组灌胃知母水煎液,连续治疗7天后,提取肝组织总RNA,应用基因芯片检测各组大鼠肝脏基因表达,筛选差异表达基因,进行基因聚类分析和功能分类注释,并选择部分差异基因进行荧光定量PCR实验验证芯片结果。
结果:PLS分析显示虚寒组和虚热组均与空白对照组样本点完全分离,得到明显区分,对虚寒模型有重要贡献的指标有:粪质地、毛发洁净度、尿色、体重、平均趾温、自主活动、饮水量、尿质地。对虚热模型有重要贡献的指标有:粪质地、粪色、平均趾温、体重、肛温、单位体重可代谢能、活动状态。基因芯片结果显示虚寒模型组与空白对照组比较有99条基因差异表达,按照Gene Ontology(GO)分类标准进行基因功能分类注释,查询到8项显著性基因功能,主要涉及免疫应答,防御应答,生物刺激应答等功能。虚寒治疗组与虚寒模型组比较有212条基因差异表达,查询到31项显著性基因功能,主要涉及免疫应答,炎症应答,防御应答,趋化因子及受体活性,氧化还原酶活性等功能。虚热模型组与空白对照组比较有99条基因差异表达,查询到5项显著性基因功能,主要涉及防御应答,固醇代谢等功能。虚热治疗组与虚热模型组比较有67条基因差异表达,查询到5项显著性基因功能,主要涉及防御应答,免疫应答,趋化因子及受体活性等功能。虚寒模型组与虚热模型组比较有114条基因差异表达,查询到4项显著性基因功能,主要涉及有机酸、羧酸合成,氧化还原酶活性等功能。对虚寒模型组与空白对照组相比较、虚热模型组与空白对照组相比较的差异基因表达谱进行分析,发现存在共有差异表达基因共28条,其中16条为免疫应答相关基因。
结论:虚寒证与虚热证模型动物的主要症状及体征与虚寒证与虚热证的临床诊断基本相符,体现了虚寒证“阳虚内寒”和虚热证“阴虚内热”的病理特点。虚寒证可能通过多种刺激应答相关基因的下调,导致免疫应答功能、防御应答功能及对其他生物体刺激应答功能的降低,虚寒证“阳气不足”的分子机制可能与此类基因的异常表达相关;附子对虚寒证大鼠免疫应答相关基因及氧化还原酶活性相关基因的调控,可能是附子“温阳散寒”作用的分子机制。虚热证“阴虚内热”的分子机制可能与刺激应答相关基因及固醇代谢相关基因两类基因的异常表达相关;知母对虚热证大鼠刺激应答相关基因表达的调控,可能是知母“滋阴”作用的分子机制。虚寒证与虚热证大鼠均出现了免疫应答相关基因表达的显著改变,这可能是虚寒证与虚热证大鼠“精气夺则虚”的分子机制。虚寒证与虚热证虽然同为虚证,但有“寒证”和“热证”不同的表现,氧化还原酶活性相关基因的异常表达可能是虚寒证与虚热证出现不同症状的分子机制。
Objective: To discuss asthenia cold syndrome rat models and asthenia hot syndrome rat models and the evaluation system to superficial characteristics fit in with throry of Traditional Chinese Medicine, the Asthenia cold syndrome rat models and asthenia hot syndrome rat models were induced by compound preparation of traditional chinese medicine, which were estimated by PLS data analysis. To analyse the molecular mechanism and the related mechanism of property and effect of Chinese medicinal herbs with hot and cold property from the view of gene expression spectrum,we study the influence of Chinese medicinal herbs with hot property such as Aconitum carmichaeli on asthenia cold syndrome rats, herbs with cold property such as Anemarrhenae Rhizoma on asthenia hot syndrome rats on whole genome expression of liver by gene chip.
Methods: The rat models were induced by compound preparation of traditional chinese medicine. Asthenia cold syndrome rats were induced by compound preparation of Raw Gypsum, Radix gentianae, Cortex Phellodendri, Anemarrhenae Rhizoma and asthenia hot syndrome rats were induced by compound preparation of Aconitum carmichaeli,Cinnamomi Cortex,Rhizoma Zingiberis once daily for 14 days. After the models were copied ,the model rats were estimated by PLS data analysis and divided into groups according to the results of analysis. Then the asthenia cold treatment group was treated by Aconitum carmichaeli,and asthenia hot treatment group was treated by Anemarrhenae Rhizoma once daily for 7 days. Seven days later,the rat liver gene expressions in each group were detected by RatRef-12 gene array made by Illumina Company. We selected the differential expression genes , analyzed the genes by cluster and conducted the significant analysis on the genetic function of differential genes. A part of genes were selected to test the accuracy of results by PCR.
Results: PLS analysis shown that the sample points of syndrome of asthenia cold syndrome group, asthenia hot syndrome group and control group was completely separated, which was clearly differentiated. The important contribution indicators to syndrome of asthenia cold model group and blank control model group were such as stool texture, hair cleanliness, urine color, weight, average toe temperature, spontaneous activity, water intake, urine texture. The important contribution indicators to syndrome of asthenia hot model group and blank control model group were such as stool texture, stool color, average toe temperature, body weight, rectal temperature, metabolic energy to unit weight, activity. There were 99 strips of differential expression gene, and 8 items of significant gene function such as immune response, defense response, response to other organism in asthenia cold model group as compared to the control group. There were 212 strips of differential expression gene, and 31 items of significant gene function such as immune response, defense response, inflammator response, oxidoreductase activity, chemokine receptor binding,chemokine activity in the asthenia cold treatment group as compared to the asthenia cold model group. There were 99 strips of differential expression gene, and 5 items of significant gene function such as defense response , sterol metabolic process in the asthenia hot model group as compared to the control group. There were 67 strips of differential expression gene and 5 items of significant gene function such as defense response, inflammatory response, chemokine receptor binding,chemokine activity in the asthenia hot treatment group as compared to the asthenia hot model group. There were 114 strips of differential expression gene, and 4 items of significant gene function such as organic and carboxylic acid biosynthetic process in the asthenia cold model group as compared to the asthenia hot model group. There were 28 strips of differential expression gene, among which 16 stips were about immune response among asthenia cold model group,asthenia hot model group and control group,.
Conclusion: The main symptoms and signs of asthenia cold syndrome and asthenia hot syndrome model animal were consistent with the clinical diagnosis of asthenia cold syndrome and asthenia hot syndrome, which reflected the pathological features of“deficient cold endogenous heat”of asthenia cold syndrome and“yin deficiency endogenous heat”of asthenia hot syndrome.Many strips of gene about response to stimulus were down-regulated in asthenia cold syndrome rats,which induced down regulation of function about immune response, defense response, response to other organism. The molecular mechanism of“insufficiency of yang qi”of asthenia cold syndrome was possibly related to these genes. The regulation of Aconitum carmichaeli on genes about immune response and oxidoreductase activity was possibly related to the molecular mechanism of“warming yang and dissipating cold”. The abnormal expression of genes about defense response and sterol metabolic process in asthenia hot syndrome rats was possibly related to the molecular mechanism of asthenia hot syndrome. The regulation of Anemarrhenae Rhizoma on genes about response to stimulus was possibly related to the molecular mechanism of“enrich yin”.The genes about immune response diffrently changed both in asthenia cold model group and asthenia hot model group,which was possibly related to the molecular mechanism of“lack of vital essence resulting in deficiency syndrome”. The abnormal expression of genes about oxidoreductase activity was possibly related to the different molecular mechanism of asthenia cold model group and asthenia hot model group.
方法:采用中药复方复制动物模型,虚寒组用生石膏、龙胆草、黄柏和知母水煎液,虚热组用熟附子、肉桂、干姜水煎液,连续灌胃14天。模型复制结束后采用PLS法对模型进行评价。虚寒组分为虚寒治疗组与虚寒模型组,其中虚寒治疗组灌胃附子水煎液,虚热组分为虚热治疗组与虚热模型组,其中虚热治疗组灌胃知母水煎液,连续治疗7天后,提取肝组织总RNA,应用基因芯片检测各组大鼠肝脏基因表达,筛选差异表达基因,进行基因聚类分析和功能分类注释,并选择部分差异基因进行荧光定量PCR实验验证芯片结果。
结果:PLS分析显示虚寒组和虚热组均与空白对照组样本点完全分离,得到明显区分,对虚寒模型有重要贡献的指标有:粪质地、毛发洁净度、尿色、体重、平均趾温、自主活动、饮水量、尿质地。对虚热模型有重要贡献的指标有:粪质地、粪色、平均趾温、体重、肛温、单位体重可代谢能、活动状态。基因芯片结果显示虚寒模型组与空白对照组比较有99条基因差异表达,按照Gene Ontology(GO)分类标准进行基因功能分类注释,查询到8项显著性基因功能,主要涉及免疫应答,防御应答,生物刺激应答等功能。虚寒治疗组与虚寒模型组比较有212条基因差异表达,查询到31项显著性基因功能,主要涉及免疫应答,炎症应答,防御应答,趋化因子及受体活性,氧化还原酶活性等功能。虚热模型组与空白对照组比较有99条基因差异表达,查询到5项显著性基因功能,主要涉及防御应答,固醇代谢等功能。虚热治疗组与虚热模型组比较有67条基因差异表达,查询到5项显著性基因功能,主要涉及防御应答,免疫应答,趋化因子及受体活性等功能。虚寒模型组与虚热模型组比较有114条基因差异表达,查询到4项显著性基因功能,主要涉及有机酸、羧酸合成,氧化还原酶活性等功能。对虚寒模型组与空白对照组相比较、虚热模型组与空白对照组相比较的差异基因表达谱进行分析,发现存在共有差异表达基因共28条,其中16条为免疫应答相关基因。
结论:虚寒证与虚热证模型动物的主要症状及体征与虚寒证与虚热证的临床诊断基本相符,体现了虚寒证“阳虚内寒”和虚热证“阴虚内热”的病理特点。虚寒证可能通过多种刺激应答相关基因的下调,导致免疫应答功能、防御应答功能及对其他生物体刺激应答功能的降低,虚寒证“阳气不足”的分子机制可能与此类基因的异常表达相关;附子对虚寒证大鼠免疫应答相关基因及氧化还原酶活性相关基因的调控,可能是附子“温阳散寒”作用的分子机制。虚热证“阴虚内热”的分子机制可能与刺激应答相关基因及固醇代谢相关基因两类基因的异常表达相关;知母对虚热证大鼠刺激应答相关基因表达的调控,可能是知母“滋阴”作用的分子机制。虚寒证与虚热证大鼠均出现了免疫应答相关基因表达的显著改变,这可能是虚寒证与虚热证大鼠“精气夺则虚”的分子机制。虚寒证与虚热证虽然同为虚证,但有“寒证”和“热证”不同的表现,氧化还原酶活性相关基因的异常表达可能是虚寒证与虚热证出现不同症状的分子机制。
Objective: To discuss asthenia cold syndrome rat models and asthenia hot syndrome rat models and the evaluation system to superficial characteristics fit in with throry of Traditional Chinese Medicine, the Asthenia cold syndrome rat models and asthenia hot syndrome rat models were induced by compound preparation of traditional chinese medicine, which were estimated by PLS data analysis. To analyse the molecular mechanism and the related mechanism of property and effect of Chinese medicinal herbs with hot and cold property from the view of gene expression spectrum,we study the influence of Chinese medicinal herbs with hot property such as Aconitum carmichaeli on asthenia cold syndrome rats, herbs with cold property such as Anemarrhenae Rhizoma on asthenia hot syndrome rats on whole genome expression of liver by gene chip.
Methods: The rat models were induced by compound preparation of traditional chinese medicine. Asthenia cold syndrome rats were induced by compound preparation of Raw Gypsum, Radix gentianae, Cortex Phellodendri, Anemarrhenae Rhizoma and asthenia hot syndrome rats were induced by compound preparation of Aconitum carmichaeli,Cinnamomi Cortex,Rhizoma Zingiberis once daily for 14 days. After the models were copied ,the model rats were estimated by PLS data analysis and divided into groups according to the results of analysis. Then the asthenia cold treatment group was treated by Aconitum carmichaeli,and asthenia hot treatment group was treated by Anemarrhenae Rhizoma once daily for 7 days. Seven days later,the rat liver gene expressions in each group were detected by RatRef-12 gene array made by Illumina Company. We selected the differential expression genes , analyzed the genes by cluster and conducted the significant analysis on the genetic function of differential genes. A part of genes were selected to test the accuracy of results by PCR.
Results: PLS analysis shown that the sample points of syndrome of asthenia cold syndrome group, asthenia hot syndrome group and control group was completely separated, which was clearly differentiated. The important contribution indicators to syndrome of asthenia cold model group and blank control model group were such as stool texture, hair cleanliness, urine color, weight, average toe temperature, spontaneous activity, water intake, urine texture. The important contribution indicators to syndrome of asthenia hot model group and blank control model group were such as stool texture, stool color, average toe temperature, body weight, rectal temperature, metabolic energy to unit weight, activity. There were 99 strips of differential expression gene, and 8 items of significant gene function such as immune response, defense response, response to other organism in asthenia cold model group as compared to the control group. There were 212 strips of differential expression gene, and 31 items of significant gene function such as immune response, defense response, inflammator response, oxidoreductase activity, chemokine receptor binding,chemokine activity in the asthenia cold treatment group as compared to the asthenia cold model group. There were 99 strips of differential expression gene, and 5 items of significant gene function such as defense response , sterol metabolic process in the asthenia hot model group as compared to the control group. There were 67 strips of differential expression gene and 5 items of significant gene function such as defense response, inflammatory response, chemokine receptor binding,chemokine activity in the asthenia hot treatment group as compared to the asthenia hot model group. There were 114 strips of differential expression gene, and 4 items of significant gene function such as organic and carboxylic acid biosynthetic process in the asthenia cold model group as compared to the asthenia hot model group. There were 28 strips of differential expression gene, among which 16 stips were about immune response among asthenia cold model group,asthenia hot model group and control group,.
Conclusion: The main symptoms and signs of asthenia cold syndrome and asthenia hot syndrome model animal were consistent with the clinical diagnosis of asthenia cold syndrome and asthenia hot syndrome, which reflected the pathological features of“deficient cold endogenous heat”of asthenia cold syndrome and“yin deficiency endogenous heat”of asthenia hot syndrome.Many strips of gene about response to stimulus were down-regulated in asthenia cold syndrome rats,which induced down regulation of function about immune response, defense response, response to other organism. The molecular mechanism of“insufficiency of yang qi”of asthenia cold syndrome was possibly related to these genes. The regulation of Aconitum carmichaeli on genes about immune response and oxidoreductase activity was possibly related to the molecular mechanism of“warming yang and dissipating cold”. The abnormal expression of genes about defense response and sterol metabolic process in asthenia hot syndrome rats was possibly related to the molecular mechanism of asthenia hot syndrome. The regulation of Anemarrhenae Rhizoma on genes about response to stimulus was possibly related to the molecular mechanism of“enrich yin”.The genes about immune response diffrently changed both in asthenia cold model group and asthenia hot model group,which was possibly related to the molecular mechanism of“lack of vital essence resulting in deficiency syndrome”. The abnormal expression of genes about oxidoreductase activity was possibly related to the different molecular mechanism of asthenia cold model group and asthenia hot model group.
引文
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