以药测证对肾虚证基因网络和信号转导的研究

总结了从细胞内的小的信号转导通路组成的网络到中等的下丘脑—垂体—肾上腺—胸腺(HPAT)轴网络和涵盖全身,联络多个重要系统的大的神经内分泌免疫(NEI)网络,提出人体受到外界干预而形成的“病”或“证”,亦都是以众多的分子网络变化为基础。描绘了信号转导通路的方式、能力、研究信号转导通路变化的方法,提出“以药测证”是按系统生物学方法研究证的干预手段。作者采用补肾复方以药测证发现肾阳虚证涵盖着NEI调节网络,而且直接作用于NEI网络的调控中枢—下丘脑。采用从补肾复方中提取的有效组分———淫羊藿总黄酮(EF),发现它通过NEI网络的下行通路激活免疫系统,能激活生长激素轴、性腺轴、淋巴细胞凋亡3个方面的网络机制发挥分子网络效应;也观察到EF调控基因网络表现出多种多样的方式,在淋巴细胞凋亡和增殖的网络机制中重塑对立的凋亡相关基因及增殖相关基因平衡;能会聚与整合共刺激分子、转化生长因子及多个原癌基因,成为启动促增殖、抗凋亡的上游因子网络;使NIK/IKK/IκB/Rel/NFκB信号转导通路中对立的IκBα与NFκB同时升高,既维持NFκB适度升高,又保证NFκB呈强者态势发挥其分子调控网络中的枢纽作用,并由此观察到肾虚证HPAT轴上有序的基因网络调控路线图谱。

英文摘要:

Three kinds of networks were summarily described in this review including the small intracellular molecular networks, the middle-scale networks of hypothalamus-pituitary-adrenal-thymus (HPAT) axis and the large network, neuroendocrine-immune (NEI) network, covering the whole organism and linking multiple systems together. The hypothesis was expressed that the “disease” or “syndrome” formed in the human body by the intervention from outside world is based on the changes of multi-molecular network. In this paper, the pattern and ability of signal transduction channel and the methods of studying changes in it were also described, and raised, herefrom, “to determine syndrome by drug effects (DSDE) ” is the intervention means for studying syndrome in the light of systemic biological methods. We found Kidney-yang deficiency syndrome covered the NEI network and the regulating center located in hypothamus with Compound Bushen Recipe (CBR, Kidney-tonifying recipe). By intervention with EF, an effective component of CBR, it was found that EF can activate the immune system and the three networks, including growth axis, sex hormone axis and lymphocyte apoptosis network in HPAT axis through the downward pathway of NEI network to play its efficiency of molecular network. There are many regulation patterns of EF on networks. For example, in the network mechanism of lymphocyte apoptosis and proliferation, EF can reconstruct the balance of the opposite apoptosis related genes and proliferation related genes; EF can assemble and integrate co-stimulating molecules, transform growth factors (TGF) , and several oncogenes to form an upstream factor network for initiating the proliferation and anti-apoptosis promotion; EF can simultaneously up-regulate the two opposite genes expression of IκB and NFκB in NIK/IKK/IκB/Rel/NFκB signal transduction channel, which could not only control the rising of NFκB in a moderate range, but also guarantee its predominant status to exert its hinge role in molecule regulating network, by which gene network regulation atlas in HPAT axis of Kidney-deficiency syndrome was observed.

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