Decoding the Key Functional Combined Components Group and Uncovering the Molecular Mechanism of Longdan Xiegan Decoction in Treating Uveitis.

Objective: Longdan Xiegan Decoction (LXD) is a famous herbal formula in China. It has been proved that LXD has been shown to have a significant inhibitory effect on suppresses the inflammatory cells associated with uveitis. However, the key functional combination of component groups and their possible mechanisms remain unclear. Methods: The community detecting model of the network, the functional response space, and reverse prediction model were utilized to decode the key components group (KCG) and possible mechanism of LXD in treating uveitis. Finally, MTT assay, NO assay and ELISA assay were applied to verify the effectiveness of KCG and the accuracy of our strategy. Results: In the components-targets-pathogenic genes-disease (CTP) network, a combination of Huffman coding and random walk algorithm was used and eight foundational acting communities (FACs) were discovered with important functional significance. Verification has shown that FACs can represent the corresponding C-T network for treating uveitis. A novel node importance calculation method was designed to construct the functional response space and pick out 349 effective proteins. A total of 54 components were screened and defined as KCG. The pathway enrichment results showed that KCG and their targets enriched signal pathways of IL-17, Toll-like receptor, and T cell receptor played an important role in the pathogenesis of uveitis. Furthermore, experimental verification results showed that important KCG quercetin and sitosterol markedly inhibited the production of nitric oxide and significantly regulated the level of TNF-α and IFN-γ in Lipopolysaccharide-induced RAW264.7 cells. Discussion: In this research, we decoded the potential mechanism of the multi-components-genes-pathways of LXD's pharmacological action mode against uveitis based on an integrated pharmacology approach. The results provided a new perspective for the future studies of the anti-uveitis mechanism of traditional Chinese medicine.

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

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-1ß, 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.