Uncovering the Molecular Mechanism of the Qiang-Xin 1 Formula on Sepsis-Induced Cardiac Dysfunction Based on Systems Pharmacology
Uncovering the Molecular Mechanism of the Qiang-Xin 1 Formula on Sepsis-Induced Cardiac Dysfunction Based on Systems Pharmacology
复制标题
基于系统药理学揭示强心1号方治疗脓毒症心功能障碍的分子机制
DOI：
10.1155/2020/3815185
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发表时间：
2020-08-27
影响因子：
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通讯作者：
Liu, Qingquan
中科院分区：
文献类型：
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作者：
He, Shasha;Zhao, Jingxia;Liu, Qingquan
心功能不全是脓毒症引起的多器官功能衰竭的重要表现，并导致脓毒症的高死亡率。我们以前的研究表明，传统中药配方，强心1（QX 1），改善脓毒症小鼠的心脏组织损伤，但其潜在的药理学机制仍有待阐明。本研究旨在阐明QX 1方对脓毒症诱导的心功能障碍的保护机制。采用盲肠结扎穿孔术建立小鼠中度脓毒症模型。用QX 1配方治疗改善了脓毒症小鼠的7天存活结果，减轻了心功能障碍，并改善了心肌结构的破坏。随后的系统药理学分析发现，从QX 1配方中筛选出63个生物活性化合物和相关的79个候选靶蛋白。网络分析表明，QX 1活性组分槲皮素、芒柄花素、山奈酚、紫杉叶素、隐丹参酮和丹参酮IIA与筛选的靶点具有较好的结合活性。整合通路分析表明，钙、PI 3 K/AKT、MAPK和Toll样受体信号通路可能参与了芪仙1方对脓毒症心功能不全的保护作用。此外，实验验证表明，QX 1配方抑制钙/钙调蛋白依赖性蛋白激酶II（CaMKII）、MAPK（P38、ERK 1/2和JNK）和TLR 4/NF-κ B信号传导途径的活性，但促进PI 3 K/AKT途径的活化。细胞因子阵列发现，QX 1配方减弱脓毒症诱导的血清IFN-γ、IL-1 β、IL-3、IL-6、IL-17、IL-4、IL-10和TNF-α的上调水平。我们的数据表明，QX 1可能代表了一种新的治疗策略，通过抑制钙，MAPK和TLR 4/NF-κ B途径的活性，但促进AKT的激活，从而控制细胞因子风暴和调节免疫平衡。本研究证明了QX 1配方的多组分、多靶点和多途径特性，并提供了QX 1配方在心功能不全相关疾病的临床应用的新认识。
Cardiac dysfunction is a critical manifestation of sepsis-induced multiorgan failure and results in the high mortality of sepsis. Our previous study demonstrated that a traditional Chinese medicine formula, Qiang-Xin 1 (QX1), ameliorates cardiac tissue damage in septic mice; however, the underlying pharmacology mechanism remains to be elucidated. The present study was aimed at clarifying the protective mechanism of the QX1 formula on sepsis-induced cardiac dysfunction. The moderate sepsis model of mice was established by cecal ligation and puncture surgery. Treatment with the QX1 formula improved the 7-day survival outcome, attenuated cardiac dysfunction, and ameliorated the disruption of myocardial structure in septic mice. Subsequent systems pharmacology analysis found that 63 bioactive compounds and the related 79 candidate target proteins were screened from the QX1 formula. The network analysis showed that the QX1 active components quercetin, formononetin, kaempferol, taxifolin, cryptotanshinone, and tanshinone IIA had a good binding activity with screened targets. The integrating pathway analysis indicated the calcium, PI3K/AKT, MAPK, and Toll-like receptor signaling pathways may be involved in the protective effect of the QX1 formula on sepsis-induced cardiac dysfunction. Further, experimental validation showed that the QX1 formula inhibited the activity of calcium/calmodulin-dependent protein kinase II (CaMKII), MAPK (P38, ERK1/2, and JNK), and TLR4/NF-kappa B signaling pathways but promoted the activation of the PI3K/AKT pathway. A cytokine array found that the QX1 formula attenuated sepsis-induced upregulated levels of serum IFN-gamma, IL-1 beta, IL-3, IL-6, IL-17, IL-4, IL-10, and TNF-alpha. Our data suggested that QX1 may represent a novel therapeutic strategy for sepsis by suppressing the activity of calcium, MAPK, and TLR4/NF-kappa B pathways, but promoting the activation of AKT, thus controlling cytokine storm and regulating immune balance. The present study demonstrated the multicomponent, multitarget, and multipathway characteristics of the QX1 formula and provided a novel understanding of the QX1 formula in the clinical application on cardiac dysfunction-related diseases.