针刺对脑衰老相关基因表达谱影响的实验研究
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摘要
随着人类寿命的延长，人口老龄化问题已引起全社会的关注。衰老及相关疾病给老人及其亲属乃至社会都带来沉重的负担，其中脑衰老更是影响老年人生活质量的首要因素。因而探讨脑衰老的机理，寻找合理的防治方法成为医学界亟待解决的问题。目前，现代医学对脑衰老机理的认识尚处于争论之中，治疗方面亦未找到有效方法。祖国医学对脑衰老的认识有其特色。导师韩景献教授针对脑衰老的肾精亏损、脾胃虚衰、瘀血停着、痰浊阻滞的病机特点确立了“益气调血、扶本培元”针法，其主穴为：膻中、中脘、气海、血海和足三里。该针法可以明显改善SAMP10老化鼠学习记忆能力，但其作用机制尚需进一步阐明。本实验采用cDNA Array技术，以快速老化模型小鼠(SAMP10)为实验对象，以正常老化小鼠(SAMR1)为对照，观察了SAMR1 7月龄对照组、SAMP10 7月龄对照组、SAMP107月龄“益气调血、扶本培元”针法组等三组之间588个基因表达的变化，以探讨SAMP10脑衰老的机制及“益气调血、扶本培元”针法改善脑衰老症状的机理。结果显示：
1．SAMP10对照组和同源正常老化SAMR1对照组相比，基因表达谱有明显差异。两组之间共有53个基因的表达发生了变化。SAMP10较正常老化有16个基因表达上调，37个基因表达下调，共涉及十二类基因。其中，(1)应激反应蛋白中细胞色素P450 1A1表达下调，谷胱甘肽S转移酶、成纤维细胞生长因子8、NF-kappa-B转录因子p65亚单位、热休克蛋白86表达上调；(2)DNA合成、重组、修复相关基因中DNA外切修复蛋白ERCC5、重组激活蛋白1表达下调，DNA修复蛋白RAD51、DNA修复蛋白RAD52表达上调；(3)神经营养因子及受体中胰岛素样生长因子Ⅱ前体、胰岛素样生长因子ⅠA、生长激素受体、雌激素受体表达下调， Ⅰ型胰岛素样生长因子受体α亚单位表达上调；(4)凋亡相关蛋白中BAX膜同功型α、蛋白激酶B、淋巴毒素受体表达下调，长型FLICE样抑制蛋白、载脂蛋白J表达上调；(5)突触相关蛋白中视磺酸受体β-2、ERBB-2受体、神经钙粘蛋白前体和突触相关蛋白90A表达下调，Ⅰ型cAMP依赖性蛋白激酶β调节链、14-3-3
蛋白 eta表达上调：（6）细胞粘联受体蛋白中 Cd14、细胞表面糖蛋白。ac－IQ
亚单位、整合素 Q 4表达下调，白细胞粘联糖蛋白 LFA－IQ 链表达上调；
（7）细胞受体中卜羟色胺IB受体、巨噬细胞集落刺激因子1受体表达下调，
白介素一7受体口表达上调；田）细胞信号传导相关基因中骨形态生成蛋白 咖
4前体、血管生成素、血管内皮生长因子前体、转化生长因子pZ前体表达
下调；（9）细胞表面抗原中CD3抗原zeta表达下调。QO）细胞骨架蛋白中1
＠
型细胞骨架角蛋白 IS表达下调；01）蛋白更新相关基因中巨噬细胞纤溶酶
原激活剂抑制因子2、基质金属蛋白酶14前体表达下调，纤溶酶原激活剂
抑制因子、金属蛋白酶抑制因子2前体表达上调；肥 转录调节因子中
Neu，。n。lhellx一1。。p一hhx pr。tehNEX一1． 干扰素诱导蛋白1、干扰素
调节因子2、Brn－3．2 POU、Engralled protein（En－2）homolog、Gbx 2、
Homeobox protein D4、PAX－8、CACCC Box－binding protein BKLF、红细
胞转录因子 NF－EZ表达下调，脑因子 1表达上调。结果提示 SAMP的脑
萎缩、学习记忆障碍等老化症状可能与下列因素有关：氧化应激水平升高；
DNA修复机制紊乱；胰岛素样生长因子系统、生长激素受体、雌激素受体
等神经营养因子及受体的夫调；凋亡调控机制紊乱；这些机制可能会导致
神经元异常凋亡增加。此外，SA）IP10脑中尚可能存在解毒功能紊乱，长时
程增强及长时程压抑调节突触传递效率失衡，突触结构异常、传递障碍及
神经递质合成异常，抗炎症、免疫吞噬等多种免疫功能障碍，5－HT受体
表达下调，巨噬细胞集落刺激回子受体介导的巨噬细胞集落刺激回子神经
保护功能降低，血管生成障碍及血脑屏障的功能失常等，从而使神经系统
的功能异常。这一结果充分体现了衰老机制的复杂性。
2．SAMP“益气调血、扶本培元”针法组与 SAM门 0对照组相比，有 56
个基因的表达不同，其中18个基因表达下调，38个基因表达上调，共涉及
十二类基因。我们发现，该针法对大多数与 SAMplo快速脑老化有关的基＠
因的表达都具有良性调整作用，即可上调由于脑衰老所造成的低表达的基
因，下调由于脑衰老所造成的高表达的基因。此外，某些基因如应激反应
蛋白中的热休克蛋白 84、凋亡相关蛋白中的 BAD蛋白、突触相关蛋白中的 台
早期生长反应蛋白 1和转录调节因子中的 AT mot i厂一结合因子 1等的表达
348
虽未表现出与SAMI，10快速脑老化有关，但是这些基因的表达爱针刺的影
响，可能参与了针刺改善SANP10脑老化症状的作用。由此我们推测：“益
气调血、扶本培元”针法改善 SAMI，的学习记忆障碍等老化症状是多途
径、多层次、多靶点的整体调整作用的结果。其机制主要包括：降低 SAMP
的氧化
As the lifespan of human being prolonged, the aging event of human is being the focus of the society. Senescence and aging related diseases are the burden of the elderly, their relative and the society. Senescence of brain is the main factor, which has effects on the life quality of the elderly. Exploring the mechanism of brain senescence, looking for the effective therapy is the main task of the medicine. Modern western medicine has been in a controversy on the mechanism of senescence, and made no breakthrough in therapy. Traditional Chinese Medicine (TCM) has much originality of understanding brain senescence. Prof. Han Jingxian established the "YiQiTiaoXue, FuBenPeiYuan" acupuncture method in terms of the pathology of brain senescence, viz. deficiency of the kidney-essence, insufficiency of the spleen and stomach, blood stasis and stagnation of phlegm. The prescription consists of Shanzhong(Renl7), Zhongwan(Renl2), Qihai(Ren6), Xuehai(SplO), Zusanli(S36). The "YiQiTiaoXue, FuBenPeiYuan" acupuncture method
can ameliorate the deficit of learning and memory in SAMP10, but the mechanisms of the therapy remain unknown. In present study, we used Senescence Accelerated Mouse (SAM) P10 and normal control SAMR1 as model, applied the cDNA Array technique, and monitored the expression difference of 588 genes in three group, viz.7-month SAMR1 control group, 7-month SAMP 10 control group, 7-month SAMP 10 "YiQiTiaoXue, FuBenPeiYuan" acupuncture method group to explore the mechanisms of brain senescence in SAMP10 and of antisenescence effect by "YiQiTiaoXue, FuBenPeiYuan" acupuncture method. The results showed:
1. 53 genes' expression was different between the 7-month SAMR1 control group(SAMRl group) and 7-month SAMP 10 control group(SAMP10 group). 16 genes' expression was upregulated and 37 genes' expression downregulated in SAMP 10 group compared to SAMR1 group. The expression changed genes included:(l) Stress response proteins: the expression of Glutathione S-transferase 5, FGF-8; Fibroblast growth factor 8, NF-kappa-B transcription factor p65 subunit (NF-kB p65), heat shock 86-kDa protein( HSP86) and 84-kDa heat shock protein (HSP84) was upregulated and Cytochrome P450 1A1 downregulated in SAMP 10 group compared to SAMR1 group. (2) DNA synthesis, recombination, and repair proteins: the expression of DNA repair
protein RAD51 homolog 1(RAD51) and yeast DNA repair protein Rad52 homolog (Rad52) was upregulated and DNA excision repair protein ERCC5 and Recombination activating protein 1 (RAG1) downregulated in SAMP 10 group compared to SAMR1 group. (3) Neurotrophic factors and receptors: the expression of Insulin-like growth factor I receptor alpha subunit was upregulated and Insulin-like growth factor II precursor, Insulin-like growth factor-IA, Growth hormone receptor and Estrogen receptor downregulated in SAMP 10 group compared to SAMR1 group. (4)Apoptosis associated proteins: The expression of FLICE-like inhibitory protein long form and Apolipoprotein J was upregulated and BAX membrane isoform alpha, Protein kinase B and Lymphotoxin receptor downregulated in SAMP 10 group compared to SAMR1 group. (5) Synapse related proteins: The expression ofcAMP-dependent protein kinase type I-beta regulatory chain and 14-3-3 protein eta was upregulated and Retinoic acid receptor beta-2, ERBB-2 receptor, PSD-95/SAP90A and Neural cadherin precursor downregulated in SAMP 10 group compared to SAMR1 group.(6)Cell adhesion receptors-proteins: The expression of Leukocyte adhesion glycoprotein LFA-1 alpha chain was upregulated and Cdl4, Cell surface glycoprotein mac-1 alpha subunit and Integrin alpha 4 downregulated in SAMP 10 group compared to SAMR1 group. (7) Cell receptors: The expression ofInterleukin-7 receptor alpha was upregulated and 5-HT receptor IB receptor and Macrophage colony stimulating factor 1 (CSF-1) receptor downregulated in SAMP10 group compared to SAMR1 group.(8) Cell signaling: The expression of Bone morphogenetic protein 4 precursor (BMP4), Placental ribonuclease inhibitor, angiogenin, Vascular endothelial growth
1．SAMP10对照组和同源正常老化SAMR1对照组相比，基因表达谱有明显差异。两组之间共有53个基因的表达发生了变化。SAMP10较正常老化有16个基因表达上调，37个基因表达下调，共涉及十二类基因。其中，(1)应激反应蛋白中细胞色素P450 1A1表达下调，谷胱甘肽S转移酶、成纤维细胞生长因子8、NF-kappa-B转录因子p65亚单位、热休克蛋白86表达上调；(2)DNA合成、重组、修复相关基因中DNA外切修复蛋白ERCC5、重组激活蛋白1表达下调，DNA修复蛋白RAD51、DNA修复蛋白RAD52表达上调；(3)神经营养因子及受体中胰岛素样生长因子Ⅱ前体、胰岛素样生长因子ⅠA、生长激素受体、雌激素受体表达下调， Ⅰ型胰岛素样生长因子受体α亚单位表达上调；(4)凋亡相关蛋白中BAX膜同功型α、蛋白激酶B、淋巴毒素受体表达下调，长型FLICE样抑制蛋白、载脂蛋白J表达上调；(5)突触相关蛋白中视磺酸受体β-2、ERBB-2受体、神经钙粘蛋白前体和突触相关蛋白90A表达下调，Ⅰ型cAMP依赖性蛋白激酶β调节链、14-3-3
蛋白 eta表达上调：（6）细胞粘联受体蛋白中 Cd14、细胞表面糖蛋白。ac－IQ
亚单位、整合素 Q 4表达下调，白细胞粘联糖蛋白 LFA－IQ 链表达上调；
（7）细胞受体中卜羟色胺IB受体、巨噬细胞集落刺激因子1受体表达下调，
白介素一7受体口表达上调；田）细胞信号传导相关基因中骨形态生成蛋白 咖
4前体、血管生成素、血管内皮生长因子前体、转化生长因子pZ前体表达
下调；（9）细胞表面抗原中CD3抗原zeta表达下调。QO）细胞骨架蛋白中1
＠
型细胞骨架角蛋白 IS表达下调；01）蛋白更新相关基因中巨噬细胞纤溶酶
原激活剂抑制因子2、基质金属蛋白酶14前体表达下调，纤溶酶原激活剂
抑制因子、金属蛋白酶抑制因子2前体表达上调；肥 转录调节因子中
Neu，。n。lhellx一1。。p一hhx pr。tehNEX一1． 干扰素诱导蛋白1、干扰素
调节因子2、Brn－3．2 POU、Engralled protein（En－2）homolog、Gbx 2、
Homeobox protein D4、PAX－8、CACCC Box－binding protein BKLF、红细
胞转录因子 NF－EZ表达下调，脑因子 1表达上调。结果提示 SAMP的脑
萎缩、学习记忆障碍等老化症状可能与下列因素有关：氧化应激水平升高；
DNA修复机制紊乱；胰岛素样生长因子系统、生长激素受体、雌激素受体
等神经营养因子及受体的夫调；凋亡调控机制紊乱；这些机制可能会导致
神经元异常凋亡增加。此外，SA）IP10脑中尚可能存在解毒功能紊乱，长时
程增强及长时程压抑调节突触传递效率失衡，突触结构异常、传递障碍及
神经递质合成异常，抗炎症、免疫吞噬等多种免疫功能障碍，5－HT受体
表达下调，巨噬细胞集落刺激回子受体介导的巨噬细胞集落刺激回子神经
保护功能降低，血管生成障碍及血脑屏障的功能失常等，从而使神经系统
的功能异常。这一结果充分体现了衰老机制的复杂性。
2．SAMP“益气调血、扶本培元”针法组与 SAM门 0对照组相比，有 56
个基因的表达不同，其中18个基因表达下调，38个基因表达上调，共涉及
十二类基因。我们发现，该针法对大多数与 SAMplo快速脑老化有关的基＠
因的表达都具有良性调整作用，即可上调由于脑衰老所造成的低表达的基
因，下调由于脑衰老所造成的高表达的基因。此外，某些基因如应激反应
蛋白中的热休克蛋白 84、凋亡相关蛋白中的 BAD蛋白、突触相关蛋白中的 台
早期生长反应蛋白 1和转录调节因子中的 AT mot i厂一结合因子 1等的表达
348
虽未表现出与SAMI，10快速脑老化有关，但是这些基因的表达爱针刺的影
响，可能参与了针刺改善SANP10脑老化症状的作用。由此我们推测：“益
气调血、扶本培元”针法改善 SAMI，的学习记忆障碍等老化症状是多途
径、多层次、多靶点的整体调整作用的结果。其机制主要包括：降低 SAMP
的氧化
As the lifespan of human being prolonged, the aging event of human is being the focus of the society. Senescence and aging related diseases are the burden of the elderly, their relative and the society. Senescence of brain is the main factor, which has effects on the life quality of the elderly. Exploring the mechanism of brain senescence, looking for the effective therapy is the main task of the medicine. Modern western medicine has been in a controversy on the mechanism of senescence, and made no breakthrough in therapy. Traditional Chinese Medicine (TCM) has much originality of understanding brain senescence. Prof. Han Jingxian established the "YiQiTiaoXue, FuBenPeiYuan" acupuncture method in terms of the pathology of brain senescence, viz. deficiency of the kidney-essence, insufficiency of the spleen and stomach, blood stasis and stagnation of phlegm. The prescription consists of Shanzhong(Renl7), Zhongwan(Renl2), Qihai(Ren6), Xuehai(SplO), Zusanli(S36). The "YiQiTiaoXue, FuBenPeiYuan" acupuncture method
can ameliorate the deficit of learning and memory in SAMP10, but the mechanisms of the therapy remain unknown. In present study, we used Senescence Accelerated Mouse (SAM) P10 and normal control SAMR1 as model, applied the cDNA Array technique, and monitored the expression difference of 588 genes in three group, viz.7-month SAMR1 control group, 7-month SAMP 10 control group, 7-month SAMP 10 "YiQiTiaoXue, FuBenPeiYuan" acupuncture method group to explore the mechanisms of brain senescence in SAMP10 and of antisenescence effect by "YiQiTiaoXue, FuBenPeiYuan" acupuncture method. The results showed:
1. 53 genes' expression was different between the 7-month SAMR1 control group(SAMRl group) and 7-month SAMP 10 control group(SAMP10 group). 16 genes' expression was upregulated and 37 genes' expression downregulated in SAMP 10 group compared to SAMR1 group. The expression changed genes included:(l) Stress response proteins: the expression of Glutathione S-transferase 5, FGF-8; Fibroblast growth factor 8, NF-kappa-B transcription factor p65 subunit (NF-kB p65), heat shock 86-kDa protein( HSP86) and 84-kDa heat shock protein (HSP84) was upregulated and Cytochrome P450 1A1 downregulated in SAMP 10 group compared to SAMR1 group. (2) DNA synthesis, recombination, and repair proteins: the expression of DNA repair
protein RAD51 homolog 1(RAD51) and yeast DNA repair protein Rad52 homolog (Rad52) was upregulated and DNA excision repair protein ERCC5 and Recombination activating protein 1 (RAG1) downregulated in SAMP 10 group compared to SAMR1 group. (3) Neurotrophic factors and receptors: the expression of Insulin-like growth factor I receptor alpha subunit was upregulated and Insulin-like growth factor II precursor, Insulin-like growth factor-IA, Growth hormone receptor and Estrogen receptor downregulated in SAMP 10 group compared to SAMR1 group. (4)Apoptosis associated proteins: The expression of FLICE-like inhibitory protein long form and Apolipoprotein J was upregulated and BAX membrane isoform alpha, Protein kinase B and Lymphotoxin receptor downregulated in SAMP 10 group compared to SAMR1 group. (5) Synapse related proteins: The expression ofcAMP-dependent protein kinase type I-beta regulatory chain and 14-3-3 protein eta was upregulated and Retinoic acid receptor beta-2, ERBB-2 receptor, PSD-95/SAP90A and Neural cadherin precursor downregulated in SAMP 10 group compared to SAMR1 group.(6)Cell adhesion receptors-proteins: The expression of Leukocyte adhesion glycoprotein LFA-1 alpha chain was upregulated and Cdl4, Cell surface glycoprotein mac-1 alpha subunit and Integrin alpha 4 downregulated in SAMP 10 group compared to SAMR1 group. (7) Cell receptors: The expression ofInterleukin-7 receptor alpha was upregulated and 5-HT receptor IB receptor and Macrophage colony stimulating factor 1 (CSF-1) receptor downregulated in SAMP10 group compared to SAMR1 group.(8) Cell signaling: The expression of Bone morphogenetic protein 4 precursor (BMP4), Placental ribonuclease inhibitor, angiogenin, Vascular endothelial growth
引文
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