Detecting Critical Functional Ingredients Group and Mechanism of Xuebijing Injection in Treating Sepsis

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.

Xuebijing injection protects against sepsis-induced myocardial injury by regulating apoptosis and autophagy via mediation of PI3K/AKT/mTOR signaling pathway in rats

“…Regulation of PI3K/AKT/mTOR pathway is mediated in the mechanism of apoptosis and autophagy, which has been confirmed in animal experiments [ 60 , 61 ]. According to a recent systemic pharmacological analysis, XBJ can affect sepsis by acting on alterations in a number of genes involved in the PI3K/AKT/mTOR signaling pathway [ 8 , 9 ]. Previous research has found that when applied to sepsis, XBJ blocked the phosphorylation of the PI3K/AKT/mTOR signaling pathway [ 62 ].…”

“…XBJ acts in both the early and late stages of sepsis by anti-inflammatory, anti-coagulation, immune regulation, vascular endothelial protection, anti-oxidative stress and other mechanisms [ 8 ]. A key response protein target coverage of 90.16% was found in the target association pattern of the phytoconstituents of XBJ with the causative genes of sepsis, demonstrating the dominancy of XBJ in the treatment of sepsis [ 9 ]. However, the underlying therapeutic mechanisms of XBJ on sepsis are still unknown, the specific mechanisms of XBJ in SIMI need to be further investigated.…”

“Three medicines and three formulas” in COVID-19: From bench to bedside

“…As the only injection in the TMTFs, XBJ is widely used in clinical practice to treat systemic inflammatory response syndrome and MODS [32][33] . Based on a large amount of clinical evidence, XBJ has significant anti-inflammatory, anti-viral, bacteriostatic, and immune-regulating effects, it has been included in the Diagnosis and Treatment Protocol for COVID-19 (Trial Version 5) to treat COVID-19 patients with severe or even critical illness [34][35] .…”

Screening of key functional components of Taohong Siwu Decoction on ischemic stroke treatment based on multiobjective optimization approach and experimental validation

“…This process has successfully helped analyze the key functional compounds and mechanisms of many prescriptions used in complex diseases [ 10 , 11 ]. For some examples, Wang figured out the key components of Chai-Hu-Shu-Gan-San and decoded the mechanism of treating depression by regulating downstream genes through protein kinase A or C to treat depression after cascade signal changes [ 12 ]; Chen found critical ingredients and mechanisms of Xuebijing injection in treating sepsis synergistically by affecting genes such as TAK1, TNF-α, IL-1β, and MEK1 in the MAPK, NF-κB, PI3K-AKT, Toll-like receptor, and TNF signaling pathways [ 13 ].…”