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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2018.01440

Network pharmacology-guided development of a novel integrative regimen to prevent acute graft-versus-host disease

 Ming Lyu1, 2,  Zhengcan Zhou1, Xiaoming Wang1, 2, Hong Lv1, 2,  Mei Wang3, Yuefei Wang1, 2, Guanwei Fan4,  Xiumei Gao1, Guixiang Pan1, 2,  Yuxin Feng1, 2* and  Yan Zhu1, 2
  • 1Tianjin University of Traditional Chinese Medicine, China
  • 2Tianjin International Joint Academy of Biomedicine, China
  • 3Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China
  • 4First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, China

Lapses in the graft-versus-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 acute GVHD 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 acute GVHD 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-κB 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-κB 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.

Keywords: Acute graft versus host disease, Network Pharmacology, Xuebijing injection, cyclosporin A, Integrative Medicine

Received: 21 Feb 2018; Accepted: 22 Nov 2018.

Edited by:

Cheorl-Ho Kim, Sungkyunkwan University, South Korea

Reviewed by:

Jing-Yan Han, Peking University, China
XIAOFEI QI, Suzhou University, China
Jihong Han, Nankai University, China
Mingfeng Zhao, Tianjin First Central Hospital, China  

Copyright: © 2018 Lyu, Zhou, Wang, Lv, Wang, Wang, Fan, Gao, Pan, Feng and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Yuxin Feng, Tianjin University of Traditional Chinese Medicine, Tianjin, China,