Network Pharmacology-Guided Development of a Novel Integrative Regimen to Prevent Acute Graft-vs.-Host Disease
Network Pharmacology-Guided Development of a Novel Integrative Regimen to Prevent Acute Graft-vs.-Host Disease
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网络药理学指导开发预防急性移植物抗宿主病的新型综合方案。
DOI：
10.3389/fphar.2018.01440
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发表时间：
2018-12-13
影响因子：
5.6
通讯作者：
Zhu, Yan
中科院分区：
文献类型：
--
作者：
Lyu, Ming;Zhou, Zhengcan;Zhu, Yan
移植物失效-vs.-同种异体造血干细胞移植（allo-HSCT）后宿主疾病（GVHD）预防和当前标准护理的副作用需要新的治疗方案。靶向T细胞的传统方法在预防急性GVHD（aGVHD）方面显示出有限的成功。系统医学在脓毒症和多器官功能障碍综合征（MODS）等复杂疾病的治疗中显示出良好的效果。采用已建立的网络药理学分析方法，我们的目的是开发新的综合方案，以防止aGVHD。我们的网络药理学分析预测血必净注射液（XBJ）针对aGVHD网络中的一系列关键节点蛋白。它还揭示了血必净配方中的一种草药丹参，它可以预防大鼠的aGVHD，与XBJ靶向的六种关键GVHD节点蛋白中的五种相同。有趣的是，网络药理学分析表明，血必净可能与临床预防aGVHD的一线药物环孢素A（CsA）具有多个aGVHD靶点。基于目前的信息，我们假设XBJ和CsA联合使用可能比单独使用任何一种药物在预防aGVHD方面产生上级效果。我们进行了体外和体内试验，以验证网络药理学分析的预测。体外实验表明，XBJ可抑制血小板聚集和巨噬细胞NF-κ B核转位。试管形成实验显示，XBJ还能促进血管生成。重要的是，CsA和XBJ的组合在拯救遭受致死性GVHD的小鼠中是有效的。XBJ通过阻止NF-κ B核转位、减轻炎症和维持巨噬细胞活力而发挥拯救作用。总体而言，网络药理学是开发新的综合方案的有力工具。联合应用XBJ和CsA对预防aGVHD有一定的临床意义。
Lapses in the graft-vs.-host disease (GVHD) prophylaxis and side effects of current standard care following allogeneic hematopoietic stem cell transplantation (allo-HSCT) call for novel regimens. Traditional approaches targeting T cells showed limited success in preventing acute GVHD (aGVHD). System medicine showed promising results treating complex diseases such as sepsis and multi-organ dysfunction syndrome (MODS). Adapting established network pharmacology analysis methods, we aimed to develop novel integrative regimens to prevent aGVHD. Our network pharmacology analysis predicted that Xuebijing injection (XBJ) targets a series of key node proteins in aGVHD network. It also unveiled that Salviae miltiorrhizae (Danshen), an herb in Xuebijing formula, which prevented aGVHD in rats, shares five out of six key GVHD node proteins targeted by XBJ. Interestingly, network pharmacology analysis indicated Xuebijing may share multiple aGVHD targets with Cyclosporin A (CsA), a first-line drug for preventing aGVHD in the clinic. Based on current information, we hypothesized that combination of XBJ and CsA may yield superior results in aGVHD prevention than either drug alone. We performed in vitro and in vivo assays to validate the predictions by the network pharmacology analysis. In vitro assays revealed XBJ prevented platelet aggregation and NF-kappa B nuclear translocation in macrophages. XBJ also promoted angiogenesis in tube-formation assay. Importantly, the combination of CsA and XBJ was effective in rescuing mice subjected to lethal GVHD. XBJ contributed to the rescue through preventing NF-kB nuclear translocation, attenuating inflammation and maintaining viability of macrophages. Overall, network pharmacology is a powerful tool to develop novel integrative regimens. Combination of XBJ and CsA may shed light on preventing aGVHD.