摘要
对于老年痴呆(AD),现在没有被认可的有效治疗手段。AD是一种经典的多因素的复杂的综合征。因此,polypharmacological或多靶点的方法可能会比单一疗法取得更好的疗效。但是,任不能确定其生物过程和涉及AD病理生理过程的生物分子会组成多靶点治疗的正确靶点。该研究提出:被不同药物扰乱的分子子网络中的co-module(由生物过程,细胞途径和节点组成)可能是AD以多靶点为基础的干预的最佳治疗靶点。基于此假说,用组成不同而对AD疗效相同的中药(TCM)处方,包括六味地黄汤(LW)、八味地黄汤(BW)、当归芍药散(DSS)、黄连解毒汤(HL)和调心方(TXF),在加速衰老小鼠prone-8(SAMP8)的海马体和大脑皮层中控制基因。我们通过cDNA微阵列研究这些基因。我们构造并解释了这些被扰乱的子网络。经过与15个基于被LW,BW,HL,DSS和TXF影响的基因的扰乱的子网络比较,结果显示被这些SAMP8小鼠的脑内干预扰乱的最重要的共同节点是RPS6KA1和FHIT,其它重要节点有UBE2D2,STUB1和AMFR。这五种药同时显著地干扰了凋亡和生物过程中蛋白质泛素化的节律。在AD的分子子网络中,这些节点和过程是药物控制的co-module的关键组成。这些结果显示,瞄准候选的凋亡和蛋白质泛素化的调控因子可能是有效的AD治疗手段,RPS6KA1,FHIT,UBE2D2,STUB1和AMFR可能是AD以多靶点为基础的治疗的最佳组合靶点。
关键词: 老年痴呆,组合靶点,分子网络,加速衰老小鼠,中药。
Current Alzheimer Research
Title:A Co-Module Regulated by Therapeutic Drugs in a Molecular Subnetwork of Alzheimer’s Disease Identified on the Basis of Traditional Chinese Medicine and SAMP8 Mice
Volume: 12 Issue: 9
Author(s): Xiao-Rui Cheng, Xiu-Liang Cui, Yue Zheng, Gui-Rong Zhang, Peng Li, Huang Huang, Yue-Ying Zhao, Xiao-Chen Bo, Sheng-Qi Wang and Wen-Xia Zhou and Yong-Xiang Zhang
Affiliation:
关键词: 老年痴呆,组合靶点,分子网络,加速衰老小鼠,中药。
摘要: There are currently no approved effective therapies for Alzheimer’s disease (AD). AD is a classic, multifactorial, complex syndrome. Thus, a polypharmacological or multitargeted approach to AD might provide better therapeutic benefits than monotherapies. However, it remains elusive which biological processes and biomolecules involved in the pathophysiologic processes of AD would constitute good targets for multitargeted therapy. This study proposes that a co-module, consisting of biological processes, cellular pathways and nodes, in a molecular subnetwork perturbed by different therapeutic drugs may be the optimal therapeutic target for an AD multitarget-based intervention. Based on this hypothesis, genes regulated in the hippocampus and cortex of senescence-accelerated mouse prone-8 (SAMP8) mice by traditional Chinese medicine (TCM) prescriptions with different constituents and the same beneficial effects on AD, including the decoctions Liu-Wei-Di-Huang (LW), Ba-Wei-Di-Huang (BW), Danggui-Shaoyao-San (DSS), Huang-Lian-Jie-Du (HL) and Tiao-Xin-Fang (TXF), were investigated via cDNA microarray, and the perturbed subnetworks were constructed and interpreted. After comparing 15 perturbed subnetworks based on genes affected by LW, BW, HL, DSS and TXF, the results showed that the most important common nodes perturbed by these interventions in the brains of SAMP8 mice were RPS6KA1 and FHIT, and that other important common nodes included UBE2D2, STUB1 and AMFR. These five drugs simultaneously and significantly disturbed the regulation of apoptosis and protein ubiquitination among biological processes. These nodes and processes were key components of the co-module regulated by therapeutic drugs in a molecular subnetwork of AD. These results suggest that targeting candidate regulator of apoptosis and protein ubiquitination might be effective for AD treatment, and that RPS6KA1, FHIT, UBE2D2, STUB1 and AMFR might be optimal combinational targets of an AD multitarget-based therapy.
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Xiao-Rui Cheng, Xiu-Liang Cui, Yue Zheng, Gui-Rong Zhang, Peng Li, Huang Huang, Yue-Ying Zhao, Xiao-Chen Bo, Sheng-Qi Wang and Wen-Xia Zhou and Yong-Xiang Zhang , A Co-Module Regulated by Therapeutic Drugs in a Molecular Subnetwork of Alzheimer’s Disease Identified on the Basis of Traditional Chinese Medicine and SAMP8 Mice, Current Alzheimer Research 2015; 12 (9) . https://dx.doi.org/10.2174/1567205012666150710111858
DOI https://dx.doi.org/10.2174/1567205012666150710111858 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
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