Table5.XLSX

Abstract

Sepsis is a systemic inflammatory reaction caused by various infectious or noninfectious factors, which can lead to shock, multiple organ dysfunction syndrome and death. It is one of the common complications and a main cause of death in critically ill patients. At present, the treatments of sepsis are mainly focused on the controlling of inflammatory response and the reduction of various organ function damage, including anti-infection, hormones, mechanical ventilation, nutritional support and traditional Chinese medicine (TCM). Among them, Xuebijing injection (XBJI) is an important derivative of TCM, which is widely used in clinical. However, the molecular mechanism of XBJI on sepsis is still not clear. The mechanism of treatment of “bacteria, poison and inflammation” and effect of multi-ingredient, multi-target and multi-pathway has still not been clarified. For solving this issue, we designed a new system pharmacology strategy which combine target genes of XBJI and the pathogenetic genes of sepsis to construct functional response space (FRS). The key response proteins in the FRS were determined by using a novel node importance calculation method and were condensed by a dynamic programming strategy to conduct the critical functional ingredients group (CFIG). Results showed that enriched pathways of key response proteins selected from FRS could cover 95.83% of enriched pathways of reference targets, which were defined as the intersections of ingredient targets and pathogenetic genes. Targets of CFIG with 60 ingredients could be enriched into 182 pathways which covered 81.58% of 152 pathways of 1,606 pathogenetic genes. The prediction of CFIG targets showed that the CFIG of XBJI could affect sepsis synergistically through genes such as TAK1, TNF-α, IL-1β and MEK1 in the pathways of MAPK, NF-κB, PI3K-AKT, Toll-like receptor and TNF signaling pathway. Finally, the effect of apigenin, baicalein and luteolin were evaluated by in vitro experiments, and were proved to effectively and significantly reduce the production of intracellular reactive oxygen species in LPS-stimulated RAW264.7 cells. These results indicate that the novel integrative model can promote the reliable and accuracy on depicting CFIGs in XBJI and figure out a methodological coordinate for the simplicity, mechanism analysis and secondary development of formulas in TCM.