Wei Penglu, Wang Pengqian, Li Bing, Gu Hao, Liu Jun, Wang Zhong
Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
Front Pharmacol. 2020 Feb 25;11:80. doi: 10.3389/fphar.2020.00080. eCollection 2020.
The variable mechanisms on additive and synergistic effects of jasminoidin (JA)-Baicalin (BA) combination and JA-ursodeoxycholic acid (UA) combination in treating cerebral ischemia are not completely understood. In this study, we explored the differential pure mechanisms of additive and synergistic effects based on pathway analysis that excluded ineffective interference.
The MCAO mice were divided into eight groups: sham, vehicle, BA, JA, UA, Concha Margaritifera (CM), BA-JA combination (BJ), and JA-UA combination (JU). The additive and synergistic effects of combination groups were identified by cerebral infarct volume calculation. The differentially expressed genes based on a microarray chip containing 16,463 oligoclones were uploaded to GeneGo MetaCore software for pathway analyses and function catalogue. The comparison of specific pathways and functions crosstalk between different groups were analyzed to reveal the underlying additive and synergistic pharmacological variations.
Additive BJ and synergistic JU were more effective than monotherapies of BA, JA, and UA, while CM was ineffective. Compared with monotherapies, 43 pathways and six functions were found uniquely in BJ group, with 33 pathways and three functions in JU group. We found six overlapping pathways and six overlapping functions between BJ and JU groups, which mainly involved central nervous system development. Thirty-seven specific pathways and 10 functions were activated by additive BJ, which were mainly related to cell adhesion and G-protein signaling; and 27 specific pathways and three functions of synergistic JU were associated with regulation of metabolism, DNA damage, and translation. The overlapping and distinct pathways and functions may contribute to different additive and synergistic effects.
The divergence pathways of pure additive effect of BJ were mainly related to cell adhesion and G-protein signaling, while the pure synergistic mechanism of JU depended on metabolism, translation and DNA damage. Such a systematic analysis of pathways may provide an important paradigm to reveal the pharmacological mechanisms underlying drug combinations.
茉莉素（JA）-黄芩苷（BA）组合及JA-熊去氧胆酸（UA）组合治疗脑缺血时相加和协同作用的机制尚不完全清楚。本研究基于排除无效干扰的通路分析，探讨相加和协同作用的差异纯机制。
将大脑中动脉闭塞（MCAO）小鼠分为八组：假手术组、溶剂对照组、BA组、JA组、UA组、珍珠母组（CM）、BA-JA组合组（BJ）和JA-UA组合组（JU）。通过计算脑梗死体积确定组合组的相加和协同作用。将基于包含16463个寡克隆的微阵列芯片的差异表达基因上传至GeneGo MetaCore软件进行通路分析和功能分类。分析不同组之间特定通路和功能串扰的比较，以揭示潜在的相加和协同药理变化。
相加作用的BJ组和协同作用的JU组比BA、JA和UA单药治疗更有效，而CM组无效。与单药治疗相比，BJ组独特地发现了43条通路和6种功能，JU组有33条通路和3种功能。我们在BJ组和JU组之间发现了6条重叠通路和6种重叠功能，主要涉及中枢神经系统发育。相加作用的BJ组激活了37条特定通路和10种功能，主要与细胞黏附和G蛋白信号传导有关；协同作用的JU组有27条特定通路和3种功能与代谢调节、DNA损伤和翻译有关。重叠和不同的通路及功能可能导致不同的相加和协同作用。
BJ相加作用的差异通路主要与细胞黏附和G蛋白信号传导有关，而JU的纯协同机制依赖于代谢、翻译和DNA损伤。这种对通路的系统分析可能为揭示药物组合潜在药理机制提供重要范例。
