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 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 research. However, the molecular mechanism of XBJI on sepsis is still not clear. The mechanism of treatment of “bacteria, poison and inflammation” and the effects of multi-ingredient, multi-target, and multi-pathway have still not been clarified. For solving this issue, we designed a new systems pharmacology strategy which combines 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). The results showed that enriched pathways of key response proteins selected from FRS could cover 95.83% of the enriched pathways of reference targets, which were defined as the intersections of ingredient targets and pathogenetic genes. The targets of the optimized 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 tumor necrosis factor signaling. Finally, the effects of apigenin, baicalein, and luteolin were evaluated by in vitro experiments and were proved to be effective in reducing the production of intracellular reactive oxygen species in lipopolysaccharide-stimulated RAW264.7 cells, significantly. These results indicate that the novel integrative model can promote reliability and accuracy on depicting the CFIGs in XBJI and figure out a methodological coordinate for simplicity, mechanism analysis, and secondary development of formulas in TCM.
Highlights
Sepsis is a systemic inflammatory response syndrome (SIRS) caused by bacteria and other pathogenic microorganisms invading the body, which can lead to shock, multiple organ dysfunction syndrome (MODS), and death
We proved that the critical functional ingredients group (CFIG) could bind proteins involved in the comprehensive pathways effectively, such as β-amyrin acetate (MOL000286), isotanshinone II (MOL007111), sitogluside (MOL000357), tanshinone IIa (MOL007154), przewaquinone B (MOL007068), and tigogenin (MOL004495) (Supplementary Figure S2)
Tanshinone IIa was detected in the Qiang-Xin 1 formula, which could be used in treating sepsisinduced cardiac dysfunction and predicted to regulate the productions of intracellular nitric oxide (NO), calcium, and mitochondrial reactive oxygen species (ROS) (Jin and Li, 2013; He et al, 2020)
Summary
Sepsis is a systemic inflammatory response syndrome (SIRS) caused by bacteria and other pathogenic microorganisms invading the body, which can lead to shock, multiple organ dysfunction syndrome (MODS), and death. A recent study estimated that the annual incidence of sepsis in the world increased to about 48.9 million, of which 11 million died, accounting for 19.70% of the total deaths in the world (Rudd et al, 2020) It is a complex and thorny problem in modern intensive care medicine, which has already posed a serious threat to human health and brought a huge burden to economic development (Liu et al, 2014; Liang et al, 2020). NF-κB could activate the cytokine storm by promoting the transcription of some pro-inflammatory cytokines, including IL-1β, IL-12, and TNF-α (Hotchkiss et al, 2016)
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